Tetrahydroquinoline derivatives as glycine antagonists

ABSTRACT

Compounds of formula (I) or a salt, or metabolically labile ester thereof wherein R represents a group selected from halogen, alkyl, alkoxy, amino, alkylamino, dialkylamino, hydroxy, trifluoromethyl, trifluoromethoxy, nitro, cyano, SO 2 R 2  or COR 2  wherein R 2  represents hydroxy, methoxy, amino, alkylamino or dialkylamino; m is zero or an integer 1 or 2; R 1  represents a group (CH 2 ) n CN, —CH═CHR 3 , (CH 2 )nNHCOCH 2 R 4  or O(CH 2 )pNR 5 R 6 ; R 3  represents cyano or the group COR 7 ; R 4  represents alkoxy or a group NHCOR 8 ; R 5  and R 6  each represent independently hydrogen or alkyl, or R 5  and R 6  together with the nitrogen atom to which they are attached represent a heterocyclic group, or R 5  is hydrogen and R 6  is the group COR 9 ; R 7  represents an alkoxy, amino or hydroxyl group; R 8  represents a hydrogen atom or optionally substituted alkyl, alkoxy, aryl or heterocyclic group; R 9  is the group R 8  or the group NR 10 R 11  wherein R 10  represents hydrogen or alkyl group; R 11  represents optionally substituted alkyl, aryl, heterocyclic or cycloalkyl group; n is zero or an integer from 1 to 4; p is an integer from 2 to 4, processes for their preparation and to their use in medicine.

[0001] This invention relates to 1, 2, 3, 4 tetrahydroquinolinederivatives, to processes for their preparation, to pharmaceuticalcompositions containing them and to their use in medicine. Inparticular, it relates to 1, 2, 3, 4 tetrahydroquinoline derivativeswhich are potent and specific antagonists of excitatory amino acids.

[0002] Carling et al., Bioorganic and Medicinal Chemistry Letters, Vol.13 pp. 65-70, 1993, teaches 4-substituted-2-carboxy tetrahydroquinolineshaving good in vitro affinity for the glycine modulatory site of theNMDA receptor complex but at best only weak in vivo activity. Moreparticularly, it teaches that such derivatives substituted at the 4position by the group CH₂CO₂H or CH₂CONHPh have little or no in vivoactivity when administered systemically (ip).

[0003] WO 97112870 and WO 98107704 describe novel4-substituted-2-carboxy-tetrahydroquinoline derivatives which not onlyhave a good in vitro affinity for the strychnine insensitive glycinebinding site associated with the NMDA receptor complex but also havegood in vivo activity when administered intravenously (iv).

[0004] We have now discovered a novel group of 4-substituted-2-carboxytetrahydroquinoline having a particularly useful profile of activity asselective antagonists for the strychnine insensitive glycine bindingsite associated with the NMDA receptor complex.

[0005] Thus the present invention provides a compound of formula (I)

[0006] or a salt or a non toxic metabolically labile esters thereof,wherein

[0007] Y represents a carbon atom;

[0008] Z is the group CH which is linked to the group Y via a doublebond and

[0009] X is CH or Z is methylene or NR₁₁ and X is a carbon atom linkedto the group Y via a double bond;

[0010] A represents a C₁₋₂ alkylene chain and which chain may besubstituted by one or two groups selected from C₁₋₆ alkyl optionallysubstituted by hydroxy, amino, C₁₋₄ alkyl amino or C₁₋₄ dialkyl amino orwhich chain may be substituted by the group=0;

[0011] R represents a halogen atom or C₁₋₄ alkyl group;

[0012] R₁ represents a hydrogen, a halogen atom or C₁₋₄alkyl group;

[0013] R₂ represents phenyl which may be substituted with up to 3 groupsselected from halogen, hydrogen, or (CH₂)_(n)R₃ wherein R₃ is COR₄,NR₆R₅, NHCOR₇, NHCONR₉R₈ or NH SO2 R₁₀ group or R₂ is a 5 memberedheteroaryl group containing 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3nitrogen atoms

[0014] R₄ represents an amino, a hydroxyl or C₁₋₄ alkoxy group;

[0015] R₅ and R₆ each independently represents hydrogen or C₁₋₄ alkylgroup or

[0016] R₅ and R₆ together with the nitrogen atom to which they areattached represent a saturated 5-7 membered heterocyclic groupoptionally containing an additional heroatom selected from oxygen,sulphur or nitrogen

[0017] R₇ represents a hydrogen atom or C₁₋₄ alkyl, C₁₋₄ alkoxy, orphenyl;

[0018] R₈ represents hydrogen or C₁₋₄alkyl group;

[0019] R₉ represents hydrogen, optionally substituted C₁₋₄ alkyl(optionally substituted by one or more hydroxy carboxyl and aminogroup), phenyl;

[0020] R₁₁ represents hydrogen or C₁₋₄ alkyl group;

[0021] R₁₀ represents hydrogen, C₁₋₄ alkyl or a nitrogen protectinggroup.

[0022] n is zero or an integer from 1 to 2;

[0023] A further embodiment of the invention provides compounds offormula (I) or a salt or a non toxic metabolically labile estersthereof, wherein

[0024] Y represents a carbon atom;

[0025] Z is the group CH which is linked to the group Y via a doublebond and

[0026] X is CH or Z is methylene or NR₁₁ and X is a carbon atom linkedto the group Y via a double bond;

[0027] A represents a C₁₋₂ alkylene chain and which chain may besubstituted by one or two groups selected from C₁₋₆ alkyl optionallysubstituted by hydroxy, amino, C₁₋₄ alkyl amino or C₁₋₄ dialkyl amino orwhich chain may be substituted by the group=0;

[0028] R represents a halogen atom;

[0029] R1 represents a hydrogen or a halogen atom;

[0030] R₂ represents phenyl which may be substituted with up to 3 groupsselected from halogen, hydrogen, or (CH₂)_(n)R₃ wherein R₃ is COR₄,NR₆R₅, NHCOR₇, NHCONR₉R₈ or NH SO2 R₁₀ group or R₂ is a 5 memberedheteroaryl group containing 1 to 3 heteroatoms selected from oxygen,sulphur and nitrogen; or 6 membered heteroaryl group containing 1 to 3nitrogen atoms

[0031] R₄ represents an amino or a hydroxyl;

[0032] R₅ and R₆ each independently represents hydrogen or C₁₋₄ alkylgroup or

[0033] R₅ and R₆ together with the nitrogen atom to which they areattached represent a saturated 5-7 membered heterocyclic groupoptionally containing an additional heroatom selected from oxygen,sulphur or nitrogen

[0034] R₇ represents a hydrogen atom or C₁₋₄ alkyl, C₁₋₄ alkoxy, orphenyl;

[0035] R₈ represents hydrogen or C₁₋₄ alkyl group;

[0036] R₉ represents hydrogen, optionally substituted C₁₋₄ alkyl(optionally substituted by one or more hydroxy carboxyl and aminogroup), phenyl;

[0037] R₁₁ represents hydrogen or C₁₋₄ alkyl group;

[0038] R₁₀ represents hydrogen, C₁₋₄ alkyl or a nitrogen protectinggroup;

[0039] n is zero or an integer from 1 to 2 with the proviso that when Xis a carbon atom linked to the group Y via a double bond then R₁ ishydrogen;

[0040] For use in medicine the salts of the compounds of formula (I)will be physiologically acceptable thereof. Other salts however may beuseful in the preparation of the compounds of formula (I) orphysiologically acceptable salts thereof. Therefore, unless otherwisestated, references to salts include both physiologically acceptablesalts and non-physiologically acceptable salts of compounds of formula(I).

[0041] Suitable physiologically acceptable salts of compounds of theinvention include base addition salts and, where appropriate, acidaddition salts. Suitable physiologically acceptable base addition saltsof compounds of formula (I) include alkali metal or alkaline metal saltssuch as sodium, potassium, calcium, magnesium and ammonium salts, formedwith amino acids (e.g. lysine and arginine) and organic bases (e.g.procaine, phenylbenzylamine, ethanolamine diethanolamine and N-methylglucosamine).

[0042] The compounds of formula (I) and/or salts thereof may formsolvates (e.g. hydrates) and the invention includes all such solvates.

[0043] The term halogen refers to a fluorine, chlorine, bromine oriodine atom. The term C₁₋₄ alkyl as used herein as a group or part of agroup refers to a straight or branched chain alkyl group containing from1 to 4 carbon atom, examples of such groups include methyl, ethyl,propyl, isopropyl, n-butyl, isobutyl, secondary butyl or tertiary butyl.

[0044] When R₂ is a 5 or 6 membered heteroaryl group this may be forexample furanyl, thiophenyl, imidazolyl, thiazolyl, oxazolyl, pyridyl orpyrimidinyl.

[0045] When R₅ and R₆ together with the nitrogen atom to which they areattached form a saturated 5-7 membered heterocyclic group optionallycontaining an additional heroatom selected from oxygen, sulphur ornitrogen this may be morpholino, 2,6 dimethylmorpholino, thiomorpholino,piperidino, pyrrolidino, piperazino or N-methylpiperazino.

[0046] When R₂ is a substituted phenyl group this is conveniently a monosubstituted phenyl group. The substituent is conveniently in the metaposition or more conveniently in the para position.

[0047] When X-Y represents a double bond, the compounds of formula (I)possess at least one asymmetric carbon atom (namely the carbon atomoccupying the 2 position of the 1, 2, 3, 4 tetrahydroquinoline ringsystem) and other asymmetric carbon atoms are possible in the group R₂.It is to be understood that all enantiomers and diastereomers andmixtures thereof are encompassed within the scope of the presentinvention.

[0048] When X-Y represents a single bond, the compounds of formula (I)possess at least two asymmetric carbon atoms (namely the carbon atomoccupying the 2 and 4 position of the 1, 2, 3, 4 tetrahydroquinolinering system) and these may be represented by the formulae (1a, 1b, 1cand 1d).

[0049] The solid wedge shaped bond indicates that the bond is above theplane of the paper and is referred to as the β configuration. The brokenindicates that the bond is below the plane of the paper and is referredto as α configuration.

[0050] Further other asymmetric carbon atoms are possible in the groupsR₂. It is to be understood that all enantiomers and diastereomers andmixtures thereof are encompassed within the scope of the presentinvention.

[0051] Non-toxic metabolically labile esters of compound of formula (I)are esters of compounds of formula (I) that are hydrolysed in vivo toafford said compound of formula I and a physiologically acceptablealcohol. Non toxic metabolically esters of compound of formula (I) maybe formed by esterification, for example of any of the carboxylic acidgroups in the parent compound of general formula (I) with, whereappropriate, prior protection of any other reactive groups present inthe molecule, followed by deprotection if required. Examples of suchmetabolically labile esters include C₁₋₄alkyl esters e.g. methyl orethyl esters, substituted or unsubstituted aminoalkyl esters (e.g.aminoethyl, 2-(N,N-diethylamino) ethyl, or 2-(4-morpholino)ethyl estersor acloxyalkyl esters such as, acyloxymethyl or 1-acyloxyethyl e.g.pivaloyloxymethyl, 1-pivaloyloxyethyl, acetoxymethyl, 1-acetoxyethyl,1-(1-methoxy-1-methyl)ethylcarbonyloxyethyl, 1-benzoyloxyethyl,isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl,cyclohexylcarbonyloxymethyl, 1-cyclohexylcarbonyloxyethyl ester,cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl,1-(4-tetrahydropyranyloxy)carbonyloxyethyl or1-(4-tetrahydropyranyl)carbonyloxyethyl.

[0052] The group R is conveniently chlorine. The group R₁ isconveniently a hydrogen or a chlorine atom.

[0053] A preferred class of compounds of formula (I) is that wherein Ris chlorine and R₁ is a hydrogen or a chlorine atom.

[0054] A further preferred class of compounds of formula (I) is thatwherein R is chlorine and R₁ is a hydrogen atom.

[0055] When X-Y is a single bound, a preferred class of compounds offormula (I) is that in which the carbon atom in 4 position is βconfiguration and the carbon atom in 2 position is in a configuration(1a) and that in which the carbon atom in 4 position is a configurationand the carbon atom in 2 position is in β configuration (1c).

[0056] When A is an optionally substituted C₁₋₂ alkylene chain this maybe, for example, methylene, ethylene or C═O.

[0057] A preferred class of compounds of formula (I) includes thosewherein A is a chain selected from —CH2—, —(CH2)2—, C═O.

[0058] When Z is a group NR₁₁ this is conveniently the group NH.

[0059] A preferred class of compounds of formula (I) includes thosewherein Z is CH which is linked to the group Y via a double bond, amethylene or a NH group.

[0060] When R₂ is an optionally substituted phenyl group this isconveniently phenyl substituted by a single substituent selected from(CH₂)_(n)NR₆R₅ in which R₅ is hydrogen and R₆ is hydrogen, C₁₋₄ alkyl(e.g. methyl, ethyl) or NR₆R₅ represents a saturated 6 membered ringcontaining oxygen e.g. morpholino; (CH₂)_(n)NHCOR₇ wherein R₇ ishydrogen, alkyl e.g. methyl, isopropyl, isobutyl, phenyl;(CH₂)_(n)NHCONHR₉ wherein R₉ is hydrogen; (CH₂)nNH SO2 R₁₀ in which R₁₀is alkyl e.g. methyl. n is zero or an integer from 1 to 2; Examples ofsuch R₂ groups include phenyl (optionally substituted by amino,t-butoxycarbonylamino, acetylamino or methanesulphonylamino)

[0061] When R₂ is substituted phenyl the substituents are convenientlyin the meta or more preferably in the para position.

[0062] When R₂ is a 5 or 6 membered heteroaryl group as above definedthis is conveniently pyridyl e.g. 3-pyridyl.

[0063] A preferred class of compounds of formula (I) is that wherein R₂represents phenyl (optionally substituted by acetylamino,methanesulphonylamino) or 3-pyridyl. Within this class those wherein R₂is phenyl are particularly preferred.

[0064] A further preferred class of compounds of formula (I) is thatwherein X is a carbon atom linked to the group Y via a double bond.

[0065] A preferred group of compounds of formula (I) is that wherein Ais is a chain selected from —CH₂— or —(CH₂)₂—, Z is a group CH which islinked to the group Y via a double bond or a methylene group, or A isthe chain CO and Z is an NH group, R is chlorine, R₁ is chlorine orhydrogen and R₂ is phenyl (optionally substituted by acetylamino ormethanesulphonylamino) or 3-pyridyl.

[0066] Specific preferred compounds of the invention include:

[0067](±)7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,

[0068](±)7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,

[0069] and physiologically acceptable salts (e.g. sodium salt) non-toxicmetabolically labile esters or enantiomers thereof.

[0070] (−)-Sodium7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate.

[0071] (−)Sodium7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate,

[0072] (+)Sodium7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2carboxylate.

[0073] Further specific preferred compounds of the invention include:

[0074](±)-7-chloro-4-(1-(3-pyridin)-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid,

[0075](±)-7-chloro-4-(1-phenyl-Δ³-5,6-dihydro-pyridin-2one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxlicacid,

[0076](±)-5,7-dichloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid,

[0077](+/−)-7-chloro-4-(1-(4-acetylamino)-1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid,

[0078](+/−)7-chloro-4-(1-(4-methanesulfonylamino)-1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid,

[0079](±)-7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid,

[0080](±)-7-chloro-4-(2,5dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid,

[0081](±)-7-chloro-4-(2-oxo-1-(pyridin-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate,

[0082](±)-7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid,

[0083] (±)7-chloro-4-(2-oxo-1-((4-methanesulfonylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid,

[0084]5,7-dichloro-4-(2-oxo-1-(phenyl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid (enantiomer A);

[0085]5,7-dichloro-4-(2-oxo-1-phenyl-Δ³-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylicacid (enatiomer A);

[0086] and physiologically acceptable salts (e.g. sodium salts),non-toxic metabolically labile esters or enantiomers thereof.

[0087] The compounds of formula (I) and/or physiologically acceptablesalts thereof are excitatory amino acid antagonists. More particularlythey are potent antagonists at the strychnine insensitive glycinebinding site associated with the NMDA receptor complex. As such they arepotent antagonists of the NMDA receptor complex. These compounds aretherefore useful in the treatment or prevention of neurotoxic damage orneurodegenerative diseases. Thus the compounds are useful for thetreatment of neurotoxic injury which follows cerebral stroke,thromboembolic stroke, hemorrhagic stroke, cerebral ischemia, cerebralvasospam, hypoglycemia, amnesia, hypoxia, anoxia, perinatal asphyxiacardiac arrest. The compounds are useful in the treatment of chronicneurodegenerative diseases such as: Huntingdon's disease, Alzheimer'ssenile dementia, amyotrophic lateral sclerosis, Glutaric Acidaemia type,multi-infarct dementia, status epilecticus, contusive injuries (e.g.spinal cord injury and head injury), viral infection inducedneurodegeration (e.g. AIDS, encephalopaties), Down syndrome, ocularneurodegeneration (e.g glaucoma), epilepsy, schizophrenia, depression,migraine, headaches including cluster headaches and or tensionheadaches, anxiety, pain (e.g inflamatory pain and neuropathic pain),neurogenic bladder, emesis irritative bladder disturbances, drugdependency, including withdrawal symptoms from alcohol, cocaine,opiates, nicotine (e.g. smoking cessation) benzodiazepines and,inhibition of tolerance induced by opioids (i.e morphine).

[0088] The potent and selective action of the compound of the inventionat the strychnine-insensitive glycine binding site present on the NMDAreceptor complex may be readily determined using conventional testprocedures. Thus the ability to bind at the strychnine insensitiveglycine binding site was determined using the procedure of Kishimoto Het al., J Neurochem 1981, 37, 1015-1024. The selectivity of the actionof compounds of the invention for the strychnine insensitive glycinesite was confirmed in studies at other ionotropic known excitatory aminoacid receptors. Thus compounds of the invention were found to showlittle or no affinity for the kainic acid (kainate) receptor,a-amino-3-hydroxy-5-methyl-4-isoxazole-proprionic acid (AMPA) receptoror at the NMDA binding site.

[0089] Compounds of the invention may be found found to inhibit NMDAinduced convulsions in mice using the procedure Chiamulera C et al.,Psychopharmacology (1990), 102, 551-552.

[0090] The neuroprotective activity of the compounds of the inventionmay be demonstrated in the middle cerebral artery occlusion preparationin mice, using the procedure described by Chiamulera C. et al., EuropeanJournal of Pharmacology, 216 (1992) pp. 335-336.

[0091] The ability of compounds of the invention to alleviate withdrawalsymptoms from nicotine following smoking cessation may be demonstratedin conventional tests of nicotine induced relapse using the proceduredescribed in C. Chiamulera et al., Arch. Pharmacol., 358, 1998.

[0092] The invention therefore provides for the use of a compound offormula (I) and/or physiologically acceptable salts or non-toxicmetabolically labile esters thereof for use in therapy and in particularuse as medicine for antagonising the effects of excitatory amino acidsupon the NMDA receptor complex.

[0093] The ability of compounds of the invention to inhibit pain may bedemonstrated in conventional analgesic screen such as those described byDubuisson and Dennis, Pain, 1977, 4:161-174; J. J. Bennett and J. K Xue,Pain, 1988, 41, 87-107.

[0094] The invention also provides for the use of a compound of formula(I) and/or a physiologically acceptable salt or non-toxic metabolicallylabile esters thereof for the manufacture of a medicament forantagonising the effects of excitatory amino acids upon the NMDAreceptor complex.

[0095] According to a further aspect, the invention also provides for amethod for antagonising the effects of excitatory amino acids upon theNMDA receptor complex, comprising administering to a patient in needthereof an antagonistic amount of a compound of formula (I) and/or aphysiologically acceptable salt thereof.

[0096] It will be appreciated by those skilled in the art that referenceherein to treatment extends to prophylactics as well as the treatment ofestablished diseases or symptoms.

[0097] It will further be appreciated that the amount of a compound ofthe invention required for use in treatment will vary with the nature ofthe condition being treated, the route of administration and the age andthe condition of the patient and will be ultimately at the discretion ofthe attendant physician. In general however doses employed for adulthuman treatment will typically be in the range of 2 to 800 mg per day,dependent upon the route of administration.

[0098] Thus for parenteral administration a daily dose will typically bein the range 20-100 mg, preferably 60-80 mg per day. For oraladministration a daily dose will typically be within the range 200-800mg, e.g. 400-600 mg per day.

[0099] The desired dose may conveniently be presented in a single doseor as divided doses administered at appropriate intervals, for exampleas two, three, four or more sub-doses per day.

[0100] While it is possible that, for use in therapy, a compound of theinvention may be administered as the raw chemical, it is preferable topresent the active ingredient as a pharmaceutical formulation.

[0101] The invention thus further provides a pharmaceutical formulationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt or non-toxic metabolically labile esters thereof together with oneor more pharmaceutically acceptable carriers thereof and, optionally,other therapeutic and/or prophylactic ingredients. The carrier(s) mustbe ‘acceptable’ in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

[0102] The compositions of the invention include those in a formespecially formulated for oral, buccal, parenteral, inhalation orinsufflaflon, implant or rectal administration.

[0103] Tablets and capsules for oral administration may containconventional excipients such as binding agents, for example, syrup,acacia, gelatin, sorbitol, tragacanth, mucilage of starch orpolyvinylpyrrolidone; fillers, for example, lactose, sugar,microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol;lubricants, for example, magnesium stearate, stearic acid, talc,polyethylene glycol or silica; disintegrants, for example, potato starchor sodium starch glycollate, or wetting agents such as sodium laurylsulphate. The tablets may be coated according to methods well known inthe art. Oral liquid preparations may be in the form of, for example,aqueous or oily suspensions, solutions emulsions, syrups or elixirs, ormay be presented as a dry product for constitution with water or othersuitable vehicle before use. Such liquid preparations may containconventional additives such as suspending agents, for example, sorbitolsyrup, methyl cellulose, glucose/sugar syrup, gelatin,hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gelor hydrogenated edible fats; emulsifying agents, for example, lecithin,sorbitan mono-leate or acacia; non-aqueous vehicles (which may includeedible oils), for example, almond oil, fractionated coconut oil, oilyesters, propylene glycol or ethyl alcohol; solubilizers such assurfactants for example polysorbates or other agents such ascyclodextrins; and preservatives, for example, methyl or propylp-hydroxybenzoates or ascorbic acid. The compositions may also beformulated as suppositories, e.g. containing conventional suppositorybases such as cocoa buffer or other glycerides.

[0104] For buccal administration the composition may take the form oftablets or lozenges formulated in conventional manner.

[0105] The composition according to the invention may be formulated forparenteral administration by injection or continuous infusion.Formulations for injection may be presented in unit dose form inampoules, or in multi-dose containers with an added preservative. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents such assuspending, stabilising and/or dispersing agents. Alternatively theactive ingredient may be in powder form for constitution with a suitablevehicle, e.g. sterile, pyrogen-free water, before use.

[0106] For administration by inhalation the compounds according to theinvention are conveniently delivered in the form of an aerosol spraypresentation from pressurised packs, with the use of a suitablepropellant, such as dichlorodifluoromethane, tirchlorofluoromethane,dichloro-tetrafluoroethane, carbon dioxide or other suitablepropellants, such as dichlorodifluoromethane, trichlorofluoromethane,dichloro-tetrafluoroethane, carbon dioxide or other suitable gases, orfrom a nebuliser. In the case of a pressurised aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.

[0107] Alternatively, for administration by inhalation or insufflation,the compounds according to the invention may take the form of a drypowder composition, for example a powder mix of the compound and asuitable carrier such as lactose or starch. The powder composition maybe presented in unit dosage form in, for example, capsules or cartridgesof e.g. gelatin, or blister packs from which the powder may beadministered with the aid of an inhaler or insufflator.

[0108] The composition according to the invention may also be formulatedas a depot preparation. Such long acting formulations may beadministered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus for example, thecompounds of the invention may be formulated with suitable polymeric orhydrophobic materials (for example as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

[0109] The compositions according to the invention may contain between0.1-99% of the active ingredient, conveniently from 30-95% for tabletsand capsules and 3-50% for liquid preparations.

[0110] Compounds of general formula (I) enantiomers and salts thereofmay be prepared by the general methods outlined hereinafter. In thefollowing description, the groups R, R₁, R₂, A, Z, X and Y are asdefined for the compounds of formula (I) unless otherwise stated.

[0111] Compounds of formula (I) and enantiomers thereof may be preparedby the cyclisation of a compound of formula (II) in which R₁₂ is acarboxylic protecting group, R₁₃ represents a bromine or iodine atom,R₁₄ represents hydrogen or a nitrogen protecting group.

[0112] followed where necessary or desired by removal of one or moreprotecting groups.

[0113] In one embodiment of this process the reaction may be carried outusing a catalytic amount of a Palladium (O) complex such astetrakis(triphenylphosphine)palladium and a suitable organic base suchas trialkylamine e.g. triethylamine or inorganic base, e.g. potassiumcarbonate.

[0114] The reaction is conveniently carded out in an aprotic polarsolvent such as acetonitrile, dimethylformamide or in aprotic apolarsolvent such as hydrocarbon (ie toluene, xilene, hexane) at atemperature within the range of 60° C. to 150° C. followed, wherenecessary or desired, by subsequent removal of the carboxyl protectinggroup R₁₂ and any protecting group R₁₄.

[0115] In a further embodiment of the process the reaction is carriedout using a catalytic amount of a Pd(II) salt such as: palladium acetateor palladium dichloride in the presence of a suitable organic base suchas trialkyl amine e.g. triethylamine and of a triarylphosphine such astriphenylphosphine.

[0116] The reaction is carried out in an aprotic solvent such asacetonitrile or dimethylformamide and preferably with heating followed,where necessary or desired, by subsequent removal of the carboxylprotecting group R₁₂ and any nitrogen protecting group R₁₄.

[0117] Compounds of formula (I) wherein X-Y is a double bond may beregioselectively prepared by carring out the cyclisation reaction in anaprotic apolar solvent such as toluene in the presence of catalyticamount of a Palladium (O) complex such astetrakis(triphenylphosphine)palladium and a suitable organic base suchas trialkylamine e.g. triethylamine or inorganic base, e.g. potassiumcarbonate.

[0118] Compounds of formula (I) wherein X-Y is a single bond may beprepared by carring out the reaction the cyclisation reaction in anaprotic polar solvent (such as acetonitrile, dimethylformamide) in thepresence of a catalytic amount of a Pd(II) salt such as: palladiumacetate or palladium dichloride in the presence of a suitable organicbase such as trialkyl amine e.g. triethylamine and of a triarylphosphinesuch as triphenylphosphine.

[0119] Suitable carboxyl protecting groups R₁₂ for use in this reactioninclude alkyl, such as ethyl, trichloroalkyl, trialkylsilylalkyl, orarylmethyl groups such as benzyl, nitrobenzyl or trityl.

[0120] Further convenient carboxyl protecting groups are those having achiral group derived from chiral alcohols such as (+)-S-indanol,(+)-S-methyl mandelate, chiral (C₁₋₄)alkyl lactate: i.e. (+)-R- or(−)-S-methly lactate, (+)-R-t-butyl lactate, (+)-R- or (−)-S-ethyllactate, (−)-S-isopropyl lactate, (−)-S-butyl lactate, (+)-R-isobutyllactate or chiral aralkyl lactate (i.e. benzyl lactate), (−)-S-perillylalcohol, (−)-methyl-(R)-3-hydroxy-2-methylpropionate, (−)-(R)-2-butanol,(−)-(S)-2-methyl-1-butanol.

[0121] R₁₂ is preferably an ethyl, benzyl group or a group derived froma chiral(C₁₋₄) alkyl lactate alcohol (eg (+)-(R)-t-butyl lactate(−)-S-butyl lactate, (+)-R-isobutyl lactate alcohol).

[0122] When R₁₄ is nitrogen protecting examples of suitable groupsinclude alkoxycarbonyl e.g. t-butoxycarbonyl, arylsulphonyl e.g.phenysulphonyl or 2-trimethylsilyiethoxymethyl.

[0123] Compounds of formula (II) may be prepared from compound offormula (III) in which R₁₂ is a carboxyl protecting group and R₁₄ ishydrogen or a nitrogen protecting group as defined in formula (II) andR₁₃ represents a bromine or iodine atom.

[0124] by reaction with an appropriate phosphorus reagent capable ofconverting the group CHO into the group:

[0125] followed, where necessary or desired, by removal of the carboxylprotecting group R₁₂ and nitrogen protecting group R₁₃.

[0126] In one embodiment of this process the reaction may be carried outusing a phoshorus ylide of formula (IV)

[0127] wherein R₁₅ is an alkyl or phenyl group.

[0128] The reaction is carried out in an aprotic solvent such asacetonitrile or dimethylformamide at a temperature ranging from −20° C.to the reflux temperature of the solvent.

[0129] Compounds of formula (III) and (IV) are either known compounds ormay be prepared by analogous methods to those used for known compounds.

[0130] A convenient method for preparing compounds of formula (III) isreacting compound of formula (V) in which R₁₂ is a carboxyl protectinggroup and R₁₄ is hydrogen or a nitrogen protecting group as defined informula (II) and R₁₃ represents a bromine or iodine atom with anallyltintrihalide. (VI) followed by ozonization reaction

[0131] The reaction conveniently takes place in a solvent such ashydrocarbon e.g. Toluene or halogenated hydrocarbon (e.g. dichforomethane at a temperature ranging from −78° C. to room temperature). Theozonization may be carried out by passing a stream of ozone into asolution in the presence of dimethyl sulphide or triphenylphosphine in asuitable solvent such as halohydrocarbon (e.g dicholoromethane) at lowtemperature e.g. −78° C.

[0132] Alternatively compounds (III) may be prepared by aldolic reactionof the imino compound (V) with the enol ether (VII), wherein R₁₆ is aC₁₋₄ alkyl group.

[0133] The reaction may be carried out in a solvent such as methylenecloruro or acetonitrile in the presence of a Lewis acid such asYtterbium triflate.

[0134] In any of the above reactions the carboxyl protecting group maybe removed by conventional procedures known for removing such groups.Thus compounds where R₁₂ is a benzyl, ethyl or (+)-R- or (−)-S-t-butyllactate group may be removed by hydrolysis using an alkali metalhydroxide e.g. lithium hydroxide or sodium hydroxide in a suitablesolvent such as ethanol or isopropanol, water or mixtures thereof,followed, where desired or necessary, by that addition of a suitableacid e.g. hydrochloric acid to give the corresponding free carboxylicacid.

[0135] In any of the above reactions the nitrogen protecting group maybe removed by conventional procedures known for removing such groups,for example by acid or base hydrolysis. Thus when R₁₄ is alkoxycarbonyle.g. t-butoxycarbonyl or phenylsulphonyl it may be removed by alkalinehydrolysis using for example lithium hydroxide in a suitable solventsuch as tetrahydrofuran or an alkanol e.g. isopropanol. Alternativelythe alkoxycarbonyl group may be removed by acid hydrolysis.

[0136] Physiologically acceptable salts of compounds of formula (I) maybe prepared by treating the corresponding acid with an appropriate basein a suitable solvent. For example the sodium or potassium salt may beprepared by treating a solution of the corresponding acid of a compoundof formula (I) with sodium or potassium 2-ethylhexanoate with alkali oralkaline metal hydroxide, or the corresponding carbonate or bicarbonatethereof. Alternatively alkali or alkaline metal salts may be prepared bydirect hydrolysis of carboxyl protected derivatives of compounds offormula (I) with the appropriate alkali or alkaline metal hydroxide.

[0137] Metabolically labile esters of compounds of formula (I) may beprepared by esterification of the carboxylic acid group or a saltthereof or by trans esterfication using conventional procedures. Thus,for example, acyloxyalkyl esters may be prepared by reacting the freecarboxylic acid or a salt thereof with the appropriate acyloxylalkylhalide in a suitable solvent such as dimethylformamide. For theesterification of the free carboxyl group this reaction is preferablycarried out in the presence of a quaternary ammonium halide such astetrabutylammonium chloride or benzyltriethylammonium chloride.

[0138] Specific enantiomers of the compounds of formula (I) may also beobtained from corresponding racemic compounds of formula (I) usingchiral HPLC procedure.

[0139] Alternatively the enantiomers may be prepared by esterificationof the corresponding racemic compounds of formula (I) with a suitablechiral alcohol, separating the resultant diastereomeric esters byconventional means e.g. chromatography or crystallisation followed byhydrolysis of the diastereomeric esters.

[0140] Suitable chiral alcohols for use in the process include(+)-S-indanol, (+)-S-methyl mandelate, chiral (C₁₋₄)alkyl lactate: i.e.(+)-R- or (−)-S-methly lactate, (+)-R-t-butyl lactate, (+)-R- or(−)-S-ethyl lactate, (−)-S-isopropyl lactate, (−)-S-butyl lactate,(+)-R-isobutyl lactate or chiral aralkyl lactate (i.e. benzyl lactate),(−)-S-perillyl alcohol, (−)-methyl-(R)-3-hydroxy-2-methylpropionate,(−)-(R)-2-butanol, (−)-(S)-2-methyl-1-butanol.

[0141] The diastereomeric esters of compounds of formula (I) may beprepared by conventional means such as reaction of the chiral alcoholwith an activated derivative of a compound of formula (I) in an aproticsolvent such as ether e.g. tetrahydrofuran.

[0142] The activated derivative of a compound of formula (I) may beprepared from compounds (I) using conventional means for preparingactivated derivatives of a carboxylic acid groups such as thoseconveniently used in peptide synthesis.

[0143] A particularly convenient method of preparing the diastereomericesters of compounds (I) is to prepare the activated derivative ofcompounds (I) in the presence of the chiral alcohol.

[0144] Thus for example racemic mixture of compounds (I) may be treatedwith the Mitsunobu combination of reagents, i.e. a dialkylazo-dicarboxylate such as diethylazodicarboxylate and a triarylphosphinee.g. triphenylphosphine or trialkylphoshine (i.e. tributylphosphine) inthe presence of the chiral alcohol.

[0145] The reaction conveniently takes place in the presence of asuitable solvent such as an ether (e.g. diethylether ortetrahydrofuran), a halohydrocarbon (e.g. dichloromethane) or a nitrile(e.g. acetonitrile) or a mixture thereof at a temperature ranging from0-30° C.

[0146] The required single diastereomeric ester of compounds (I) may beobtained from the mixture thereof by conventional means, for example bythe use of conventional chromatographic procedures such as preparativeHPLC or by fractional crystallization.

[0147] Alternatively the required single diastereomeric ester ofcompound of formula (I) may be obtained using a suitable chiralprotecting group R₁₂ as defined in formula (II).

[0148] Specific enantiomers of compounds of formula (I) may be preparedfrom the corresponding single diastereomeric ester of compounds (I) byhydrolysis e.g. alkaline hydrolysis. Thus, for example, the hydrolysismay be carried using an alkali metal hydroxide e.g. sodium hydroxide orlithium hydroxide in a solvent such as an ether e.g. tetrahydrofuran andwater.

[0149] Alternatively specific enantiomers of compounds of formula (I)may be prepared by stereoselective enzymatic hydrolysis of compounds offormula (VIII)

[0150] Wherein R₁₇ is a carboxyl protecting group Suitable carboxylprotecting group R₁₇ for use in this reaction include C₁₋₄ alkyl such asmethyl, ethyl, propyl, butyl, or arylmethyl groups such as benzyl,nitrobenzyl or trityl.

[0151] Suitable enzymes for use in this reaction are lipase enzymes suchas Aspergillus niger (AP-12) lLipase-DS (Aspergillus niger, Amano),Candida rugosa lipase (Amano), Candida cylindracea lipase (Amano),Alcaligenes sp. lipase, Rhizopus arrhizus lipase (Biotal), Wheat germlipase (Sigma), Rhizopus niveus lipase (Amano), Promod 21 5-P protease(Biocatalyst), lipase E-7 (Themogen), lipase E-17 (Thermogen). Furthersuitable enzymes which may be used in this reaction are porcinepancreatic lipase, alpha-chymotrypsin or trypsin.

[0152] A particular preferred enzyme for use in this reaction isAspergillus niger (AP-12).

[0153] Resting cells of the following organisms may also be used in thisreaction Aspergillus ochraceus, Aspergillus niger, Aspergilluschevalieri & Aspergillus cervinus.

[0154] The reaction is conveniently carried out in an aprotic solventsuch as DMSO, tetrahydrofuran in the presence of a suitable aqueousbuffer (i.e. phosphate buffer or CaCl2. If required a solubilising agentsuch as Tween-80 may be added to the reaction mixture.

[0155] In a further process the enzyme may be immobilized and thereaction is carried out in essentially “neat” water-saturated organicsolvents such as methyl tert-butyl ether or tert-amyl alcohol.

[0156] In order that the invention may be more fully understood thefollowing examples are given by way of illustration only.

[0157] In the Intermediates and Examples unless otherwise stated:

[0158] Melting points (m.p.) were determined on a Gallenkamp m.p.apparatus and are uncorrected. All temperatures refer to ° C. Infraredspectra were measured on a FT-IR instrument. Proton Magnetic Resonance(¹H-NMR) spectra were recorded at 400 MHz, chemical shifts are reportedin ppm downfield (d) from Me₄Si, used as internal standard, and areassigned as singlets (s), doublets (d), doublets of doublets (dd),triplets (t), quartets (q) or multiplets (m). Column chromathography wascarried out over silica gel (Merck AG Darmstaadt, Germany). Thefollowing abbreviations are used in text: EA=ethyl acetate,CH=cyclohexane, DCM=dichloromethane, THF=tetrahydrofuran,TFA=trifluoroacebc acid, TEA=triethylamine, DMF=dimethylformamide,ACO=acetic anhydride, PPA=polyphosphoric acid, DBU=1,8-diazobicyclo[5,4,0]undec-7-ene, DMSO=dimethylsulphoxide, IMS=mixture of Ethanol with5% of methanol, LHDMS=Lithiumbis(trimethylsilyl)amide.DIPEA=diisopropylethylamine Tlc refers to thin layer chromatography onsilica plates, and dried refers to a solution dried over anhydroussodium sulphate; r.t. (RT) refers to room temperature.

[0159] Enantiomer A or diastereoisomer A refer to a single enatiomer ora single diastereoisomer respectively whose absolute stereochemistry wasnot characterized.

[0160] Intermediate 1

[0161] (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-pentenoate

[0162] To a solution of 2-iodo 4 chloro aniline (9.1 g) in dry toluene(150 ml) ethyl glyoxylate (50% solution in toluene, 14.6 ml) and MgSO₄(2 g) were added and the resulting suspension was refluxed overnight. Itwas then filtered and concentrated to dryness under high vacuum at 50°C. for 1.5 h. The resulting brown oil was dissolved in dichloromethane(150 ml) cooled to −78° C. and TiCl₄ (99.995% purity, 4 ml) was addedvia syringe.

[0163] The suspension was stirred 15 min at −78° C., then allowed towarm to rt over 15 min before being cooled again to −78° C.Allyltributyltin (17 ml) was then added and the reaction allowed toproceed for 1 h. The black solution was poured into 200 ml of ethylacetate and washed first with a saturated solution of NH₄Cl (2×150 ml),then with water and brine. The organic phase was dried and concentratedto give the crude product, which was purified by column chromatography(cyclohexane, then cyclohexanelethyl acetate 98/2) to give the titlecompound (10.4 g) as a colourless oil.

[0164] NMR (CDCl₃) δ (ppm) 7.57 (d, 1H), 6.49 (dd, 1H), 6.45 (dd, 1H),5.79 (m, 1H), 5.25 (dd, 1H) 5.24 (dd, 1H), 4.83 (d, 1H), 4.25 (q, 2H),4.13 (m, 1H), 2.66 (m, 2H), 1.30 (t, 3H)

[0165] Intermediate 2

[0166] (±)-Ethyl 2-(5-chloro-2-iodoanilino)-4-oxobutanoate

[0167] A solution of intermediate 1 (5.2 g) in dichloromethane (150 ml)was cooled to −78° C. and ozone was bubbled through it until the clearsolution became brick-red. At this point the flux of ozone wasinterrupted and the solution was purged with nitrogen for a few minutes.Triphenyl phosphine (7.1 g) was added and stirring continued for 1.5 h,without control of the temperature. The resulting solution was pouredinto 200 ml of ethyl acetate and washed first with a saturated solutionof NH₄Cl (2×150 ml), then with water and brine. The organic phase wasdried and concentrated to give the crude product, which was purified bycolumn chromatography (cyclohexanelethyl acetate 80/20) to give thetitle compound (2.4 g) as a colourless oil.

[0168] NMR (DMSO) δ (ppm) 9.80 (t, 1H), 7.57 (d, 1H), 6.55 (d, 1H), 6.51(dd, 1H), 4.99 (d, 1H), 4.46 (m, 1H), 4.24 (q, 2H), 3.08 (m, 2H), 1.28(t, 3H)

[0169] Intermediate 2a

[0170] (±) Ethyl 2-(3,5-dichloro-2-iodoanilino)-4-oxobutanoate

[0171] A solution of ethyl glyoxylate (50% solution in toluene, 1 ml)and MgSO₄ (7 g) in toluene (30 ml) was refluxed in Dean-Stark apparatusfor 0.5 hrs.

[0172] Then, 3,5,-chloro-2iodoaniline was added, and the mixturerefluxed for 1 hr. Then mixture was cooled, filtered through celite toeliminate the MgSO4, and concentrated. The resulting brown oil wasdissolved in dichloromethane (15 ml) cooled to −78° C. and Yb(OTf)₃xH₂O(0.186 g) was added. The suspension was stirred for 5 mins at −78° C.,then the vinyloxytrimethylsilane (0.29 g) was added and the temperaturewas risen to 20° C. After 1 hr at that temperature a saturated solutionof NH4Cl (20 cc) was added followed by ethyl acetate (30 ml). Theorganic phase was washed with brine (20 ml) and dried over sodiumsulphate and concentrated to give the crude product, which was purifiedby column chromatography (cyclohexane, then cyclohexane/ethyl acetate85/15) to give the title compound (0.562 g) as a colourless oil.

[0173] NMR (CDCl₃) δ (ppm) 9.65 (s, 1H), 7.00 (d, 1H), 6.70 (d, 1H),5.60 (d, 1H), 4.80 (m, 1H) 4.10 (q, 2H), 3.10 (m, 2H), 1.15 (t, 3H).

[0174] Intermediate 3

[0175] Tributyl (2oxo-1-phenylpyrrolidin-1-yl) phosphonium Bromide

[0176] N,N,N¹N¹-Tetramethylethylene diamine (23.3 ml) was added to asolution of N-phenylpyrrolidinone (5 g) in dichloromethane (50 ml). Thesolution was cooled to 0-5° and trimethylsilyl triflate (8.4 ml) wasadded over ca 20 mins maintaining the temperature in the range 0-5°. Theresultant solution was stirred for 10 mins and a solution of pyridiniumbromide perbromide (13 g) in acetonitrile (20 ml) was added over ca 20mins maintaining the temperature in the range 0-10°. The resultantsuspension was stirred at 0-5° for ca 60 mins. Aqueous sodiumbicarbonate solution (50 ml) was added, cautiously. The mixture wasstirred for ca 5 mins and the layers are separated. The aqueous phasewas diluted with water (20 ml) and back extracted with dichloromethane(20 ml). The combined organic phases were washed with further sodiumbicarbonate solution (50 ml), 2M hydrochloric acid (2×50 ml) and water(50 ml), back extracting each wash with dichloromethane (10 ml). Theorganic solution was dried (MgSO₄) and concentrated on a rotavapor. Thered/brown solid was stirred with ethyl acetate (50 ml) and warmed togive a solution which was then cooled and tributylphosphine (8.5 ml) wasadded. The solution was heated to reflux and maintained at reflux for2.5 hours. The solution was allowed to cool to room temperature and wasthen cooled to 0-5°. The resulting suspension was aged at 0-5° for ca 60min. The product was isolated by vacuum filtration and then washed withethyl acetate:t-butyimethylether (1:1, 40 ml) and dried in a vacuum ovenat 45° to give the title compound as a white crystalline solid (10.12g), mp 127-128°.

[0177] Intermediate 4

[0178] (±) E-Ethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)butanoate (4a);(±)-Z-Ethyl2-(5-chloro-2-iodoanilino)-4-(2oxo-1-phenyl-3-pyrrolidinylidene)Butanoate(4b)

[0179] To a solution of intermediate 2 (2.4 g) in acetonitrile (100 ml)at r.t. intermediate 3 (3.7 g) and DBU (13 ml) were added and stirringwas continued overnight at −20° C. The crude solution was poured into200 ml of ethyl acetate and washed with a saturated solution of NH₄Cl(2×150 ml), then with water and brine. The organic phase was dried andconcentrated to give the crude product as a 4/1 mixture of 4a/4bcompounds. Purification by column chromatography (cyclohexanelethylacetate 80/20) gave the title 4a (2.16 g) and the 4b (0.5 g) compoundsas colourless oils.

[0180] Intermediate 4a

[0181] NMR (CDCl₃) δ (ppm) 7.72 (d, 2H), 7.56 (d, 1H), 7.38 (t, 2H),7.16 (t, 1H), 6.6 (m, 1H), 6.50 (dd, 1H), 6.49 (d, 1H), 4.88 (d, 1H),4.26 (m, 3H), 3.87 (t, 2H), 2.79 (m, 4H), 1.30 (t, 3H)

[0182] Intermediate 4b

[0183] NMR (CDCl₃) δ (ppm) 7.69 (d, 2H), 7.52 (d, 1H), 7.38 (t, 2H),7.17 (t, 1H), 6.47 (d, 1H), 6.44 (dd, 1H), 5.98 (m, 1H), 5.00 (d, 1H),4.22 (m, 2H), 4.13 (m, 1H), 3.84 (t, 2H), 3.2-3.6 (m, 2H), 2.85 (m, 2H),1.26 (t, 3H)

[0184] Intermediate 5

[0185](1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-pentenoate(5a) and(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-pentenoate(5b)

[0186] A solution of intermediate1-tert-butyl-(R)-2(oxoacetoxy)-2-methyl acetate (4.1 g) in toluene (200ml) was refluxed in a Dean-Stark apparatus for 2 hrs. After cooling toroom temperature, 5-chloro-2-iodoaniline (4.3 g) was added, and thesolution refluxed in the presence of MgSO₄ for 3 hrs. The clear solutionwas cooled, filtered through cotton to eliminate the MgSO₄, concentratedto dryness and re-dissolved in dichloromethane (150 ml). The solutionwas cooled to −78° C., and TiCl₄ (1.9 ml) was added slowly from asyringe. After 15 min, allyl tributyltin (7.9 ml) was added, and theresulting black suspension was stirred for 1 hr. It was then poured ontoethyl acetate (300 ml), and saturated NH₄Cl (150 ml) was added. Theorganic phase was separated, washed with water and brine, dried andconcentrated. Final purification by column chromatography(cyclohexanelethyl acetate 95/5) afforded the title compound (4.1 g)(65/35 mixture of diastereomers) as a colourless oil (7.01 g)

[0187] NMR (CDCl₃) δ (ppm) 7.54 (1H), 6.46 (dd, 1H), 5.86 (m, 1H),5.3-5.2 (m, 2H), 5.03 (m, 1H), 4.77 (bd, 1H), 4.16 (m, 1H), 2.8-2.68 (m,2H), 1.50 (d, 3H), 1.45 (s, 9H)

[0188] Intermediate 5a

[0189](1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-pentenoate

[0190] To a solution of allyltributyl tin (3.3 g) in dry DCM (100 ml) a1M solution in DCM of SnCl₄ (10 ml) was added at −78° C. The mixture wasstirred for 20 min, then intermediate2-[2-(5-Chloro-2-iodo-phenylimino)-acetoxy]-1-(R)-methyl-acetic acidterbutyl ester (2.39 g) in dry DCM (50 ml) was added. The reaction wasallowed to react at −78° C. for 20 min, then a saturated solution ofNH4Cl was added and the resulting mixture was extracted with ethylacetate (2×200 ml). The organic layer was washed with a solution of KF10% in water, then diethyl ether was added and the resulting solid wasfiltered.

[0191] The solution was dried and evaporated under vacuum. Finalpurification by flash chromatography (CH/EA 95:5) give the titlecompound as pure diastereomer as a colourless oil (1.3 g).

[0192] NMR (CDCl3): 7.55 (d, 1H); 6.47 (d, 1H); 6.43 (d, 1H); 5.88 (m,1H); 5.27 (m, 2H); 5.05 (q, 1H); 4.78 (d, 1H); 4.18 (m, 1H0; 2.74 (m,2H); 1.52 (d, 3H); 1.67 (s, 9H).

[0193] IR (CDCl3): 3379, 1740

[0194] Intermediate 6

[0195](1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-oxobutanoate(6a) and(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2(5-chloro-2-iodoanilino)-4-oxobutanoate(6b)

[0196] A solution of intermediate 5 (7.1 g) in dichloromethane (200 ml)was cooled to −78° C. and ozone was bubbled through it until thesolution turned red. Triphenylphosphine (8 g) was then added, and thereaction allowed to stir for 2 hrs, without control of the temperature.The crude mixture was evaporated to dryness and purified repeatedly bycolumn chromatography ((cyclohexanelethyl acetate 85/15) to afford thetitle compound 6a (2.75 g) and 6b (0.87 g) as colourless oils.

[0197] compound 6a:

[0198] NMR (CDCl₃) δ (ppm) 9.85 (t, 1H), 7.57 (d, 1H), 6.58 (d, 1H),6.51 (dd, 1H), 5.04 (q, 1H), 4.96 (d, 1H), 4.62 (m, 1H), 3.13 (dd, 2H),1.55-1.42 (m, 12 H)

[0199] IR (CDCl3) (cm⁻¹) 1740

[0200] compound 6b:

[0201] NMR (CDCl₃) δ (ppm) 9.81 (t, 1H), 7.57 (d, 1H), 6.60 (d,1H), 6.52(dd, 1H), 5.02 (q, 1H), 4.95 (d, 1H), 4.55 (m, 1H), 3.11 (m, 2H),1.55-1.43 (m, 12H).

[0202] IR (CDCl3) (cm⁻¹) 1740

[0203] Intermediate 6a

[0204](1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl-2-(5-chloro-2-iodoanilino)-4-oxobutanoate

[0205] The title compound was obtained starting from intermediate 5afollowing the same procedure described for intermediate 6.

[0206] Intermediate 7

[0207] (E)-(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)butanoate(Diastereoisomer A)

[0208] To a solution of intermediate 6a (2.7 g) in acetonitrile (60 ml)2b (3 g) and DBU (1 ml) were added and the mixture was reacted at −20°C. overnight. It was then taken up with ethyl acetate (300 ml) andwashed with 1N HCl, water and brine, dried and concentrated. Finalpurification by column chromatography (cyclohexanelethyl acetate 85/15)afforded the title compound (2.1 g) as a white solid.

[0209] m.p. 36-39°, [α]_(D) 22° (c=0.160% w/v in DMSO)

[0210] NMR (CDCl₃) δ (ppm) 7.72 (d, 2H), 7.55 (d, 1H), 7.38 (t, 2H),7.15 (t, 1H), 6.66 (m, 1H), 6.49 (dd, 1H), 6.48 (d, 1H), 5.05 (m, 1H),4.81 (d, 1H), 4.30 (m, 1H), 3.87 (t, 2H), 3.0 (m, 2H), 2.75 (m, 2H),1.51 (d, 3H), 1.45 (s, 9H).

[0211] Intermediate 8

[0212] (−)-(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl7-chloro-4-(1-phenyl-Δ³-pyrrolin-2one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate(8a)

[0213](−)7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinoline2-carboxylic acid, [1-(R)-(1-tert-butoxycarbonyl)]ethyl Ester (8b)

[0214] To a solution of intermediate 7 (2.1 g) in DMF (40 ml) Pd(PPh₃)₄(0.393 g) and triethylamine (0.95 ml) were added and the mixture washeated to 150° C. for 1 hr. The crude solution was taken up with ethylacetate and washed with 1N HCl, water and brine, dried and evaporated.Final purification by column chromatography(cyclohexane/dichloromethanelethyl acetate 50/40/10) afforded the titlecompound 8a (0.7 g) as a white solid.

[0215] m.p.=69-73° C.

[0216] [α]_(D)−70.1° (c=0.190% w/v in DMSO)

[0217] NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.12 (m, 1H), 6.82(d, 1H), 6.77 (d, 1H), 6.70 (m, 1H), 6.49 (dd, 1H), 6.46 (bs, 1H), 4.93(q, 1H), 4.49 (m, 2H), 4.02 (m, 1H), 3.87 (m, 1H), 2.44 (m, 1H), 2.00(m, 1H), 1.39 (s, 9H), 1.38 (d, 3H).

[0218] IR (Nujol) (cm⁻¹) 3380, 1741, 1681, 1601 and the title compound8b (0.8 g) as a yellow solid.

[0219] m.p.=59-64° C.

[0220] [α]_(D)−76.2° (c=0.510% w/v in DMSO)

[0221] NMR (DMSO) δ (ppm) 7.73 (m, 2H), 7.36 (m, 2H), 7.21 (d, 1H), 7.11(m, 1H), 6.98 (da, 1H), 6.75 (d, 1H), 6.57 (dd, 1H), 4.70 (q, 1H), 4.24(m, 2H), 3.84 (m, 1H), 3.75 (m, 1H), 3.18 (m, 1H), 3.05 (m, 1H), 2.94(m, 1H), 1.25 (s, 9H), 1.23 (d, 3H)

[0222] Intermediate 9

[0223] (±)-E-Ethyl 2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenylpiperidinylidene) Butanoate

[0224] To a solution of tributyl-3-(1-phenyl-2-piperidinone) phosphoniumbromide (0.83 g) in acetonitrile (20 ml) DBU (0.27 ml) was added andafter 15 min a solution of the intermediate 2 (0.35 g) in acetonitrile(20 ml). The reaction mixture was stirred for 30 min, then diluted withethyl acetate and washed with a 1N solution of HCl and brine. Theorganic phase was dried and concentrated to give the crude product whichwas purified by flash column chromatography to obtain the title compound(0.29 g) as pale yellow foam.

[0225] NMR (CDCl₃) δ (ppm) 7.56 (dd, 1H), 7.38 (dd, 2H), 7.27 (dd, 2H),7.24 (t, 1H), 6.93 (t, 1H), 6.50-6.47 (m, 2H), 4.85 (d, 1H), 4.25 (q,2H), 4.22 (m, 1H), 3.71 (m, 2H), 2.76, (m, 2H), 2.59 (m, 2H), 2.01 (m,2H), 1.29 (t, 3H)

[0226] Intermediate 10

[0227] (±)-Ethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-(pyridin-3-yl)-pyrrolidin-3-ylidene)butanoate

[0228] To a solution of the (1-(pyridin-3-yl)-2-oxo-pyrrolidin-3-yl)tributylphosphonium bromide (0.93 g) in acetonitrile (10 ml) DBU (0.22ml) was added and after 10 min a solution of the intermediate 2 (0.46 g)in acetonitrile (10 ml). The reaction mixture was stirred for 3 hr. thendiluted with ethyl acetate and washed with a saturated solution of NH₄Cland brine. The organic phase was dried and concentrated to give thecrude product which was purified by flash column chromatography toobtain the title compound (0.47 g) as a mixture of E/Z isomer (80/20)

[0229] MS (m/z) 526

[0230] Intermediate 11

[0231] (±)-E-Ethyl2-(3,5-dichloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)Butanoate (11a);(±)-Z-Ethyl2-(3,5-dichloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)Butanoate (11b)

[0232] To a solution of intermediate 2a in acetonitrile (10 ml) at r.t2b (0.726 g) and DBU (0.33 ml) were added and stirring was continuedovernight at −20° C. The crude solution was poured into 20 ml of ethylacetate and washed first with a saturated solution of NH₄Cl (2×15 ml),then with water and brine. The organic phase was dried and concentratedto give the crude product as a 4/1 mixture of Z/E isomers. Purificationby column chromatography (cyclohexane/ethyl acetate 85/15) gave thetitle compound 11a (0.498 g) and the title compound 11b (0.122 g) ascolourless oils.

[0233] intermediate 11a

[0234] NMR (CDCl₃) δ (ppm) 7.78 (d, 2H), 7.39 (t, 2H), 7.16 (t, 1H),6.90 (d, 1H), 6.58 (m, 1H), 6.36 (d, 1H), 5.22 (d, 1H), 4.26 (m, 3H),3.87 (t, 2H), 2.79 (m, 4H), 1.30 (t, 3H)

[0235] IR (CDCl3) (cm⁻¹) 3370, 1738, 1697, 1671.

[0236] MS (m/z) 559.

[0237] intermediate 11b

[0238] NMR (CDCl₃) δ (ppm) 7.69 (d, 2H), 7.38 (t, 2H), 7.17 (t, 1H),6.84 (d, 1H), 6.34 (d, 1H), 5.96 (m, 1H), 5.34 (d, 1H), 4.22 (m, 2H),4.12 (m, 1H), 3.84 (t, 2H), 3.63-3.27 (m, 2H), 2.85 (t, 2H), 1.26 (t,3H)

[0239] IR (CDCl3) (cm⁻¹) 1733, 1685.

[0240] MS (m/z) 559.

[0241] Intermediate 12

[0242] -(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)butanoate(Diastereoisomer B)

[0243] To a solution of intermediate 6b (0.87 g) in acetonitrile (20 ml)tributyl-3-(N-phenyl-1-pyrrolidonyl)phosphonium bromide (1.6 g) and DBU(0.33 ml) were added and the mixture was reacted at −20° C. overnight.It was then taken up with ethyl acetate (100 ml) and washed with 1N HCl,water and brine, dried and concentrated. Final purification by columnchromatography (cyclohexanelethyl acetate 85/15) afforded the titlecompound (0.47 g) as a white solid oil.

[0244] m.p.=38-42° C.

[0245] NMR (CDCl₃) δ (ppm) 7.72 (d, 2H), 7.55 (d, 1H), 7.38 (t, 2H),7.16 (t, 1H), 6.60 (m, 1H), 6.56 (d, 1H), 6.49 (dd, 1H), 5.03 (q, 1H),4.80 (d, 1H), 4.33 (m, 1H), 3.88 (t, 2H), 2.9 (m, 2H), 2.75 (m, 2H),1.48 (d, 3H), 1.44 (s, 9H).

[0246] IR (CDCl3) (cm⁻¹) 3375, 1738, 1693, 1665

[0247] Intermediate 13

[0248] -(1R)-2-(tert-butoxy)-1-methyl-2-oxoethyl7-chloro-4-(1-phenyl-Δ³-pyrrolin-2one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate(diastereoisomer B)

[0249] To a solution of intermediate 12 (0.46 g) in DMF (8 ml) Pd(PPh₃)₄(0.043 g) and triethylamine (0.21 ml) were added and the mixture washeated to 150° C. for 1 hr. The crude solution was taken up with ethylacetate and washed with 1N HCl, water and brine, dried and evaporated.Final purification by column chromatography(cyclohexane/dichloromethane/ethyl acetate 50/40/10) afforded the titlecompound (0.114 g) as a white solid.

[0250] m.p.=62-67° C.

[0251] NMR (DMSO) δ (ppm) 7.79 (m, 2H), 7.38 (m, 2H), 7.11 (t, 1H), 6.81(d, 1H), 6.77 (d, 1H), 6.70 (d, 1H), 6.55 (bs, 1H), 6.48 (dd, 1H), 4.90(q, 1H), 4.5 (m, 2H), 3.99 (m, 1H), 3.84 (t, 1H), 2.35 (m 1H), 2.02 (m,1H), 1.39 (s, 12H).

[0252] Intermediate 14

[0253] 2,4-dibromo-N-(4-(tert-butoxycarbonylamino)phenyl)-butyramide

[0254] To the derivative 2,4-dibromobutyryl bromide (3.1 g) in drydichloromethane (60 ml) pyridine (3.2 ml) was added, the mixture waskept at 0° C. under a nitrogen atmosphere for 10 minutes and then theN-t-butoxy carbonyl-1,4 phenylene diamine (2.08 g) was dropped. After 1hour the mixture was poured into a saturated solution of NH₄Cl (200 ml)extracted with EA (3×150 ml) and the organic phase washed with brine(200 ml), dried and concentrated in vacuum, the crude was purified byflash chromatography (eluting with CH/EA 80: 20) to give of the titlecompound as a yellow foam (3.5 g). T.l.c. CH/EA 8:2, R_(f)=0.53.

[0255]¹H-NMR: 7.89 (sa); 7.44 (d); 7.35 (d); 6.46 (sa); 4.66 (dd); 3.60(m); 2.76(m); 2.55(m); 1.51(s).

[0256] Intermediate 15

[0257] 3-bromo-1-(4-(tert-butoxyarbonylamino)phenyl-2-oxo-pyrrolidine

[0258] To a solution of intermediate 14 (3.5 g) in dry THF (50 ml)cooled (0° C.), a solution of LHMDS (9.6 ml of a 1M solution intetrahydrofuran) was added drop-wise. The mixture was stirred undernitrogen until the temperature reached r.t for 2 hours. Then it wasquenched into a saturated solution of NH₄Cl (200 ml) extracted with EA(3×150 ml) and the organic extracts were washed with brine (200 ml),dried and concentrated in vacuum. The mixture was purified by flashchromatography (eluting with CH/EA 8:2) to give the title compound (2.6g). T.l.c. CH/EA 8:2, R_(f)=0.31. ¹H-NMR: 7.57 (d); 7.39 (d); 6.49 (sa);4.59 (m); 4.03 (m); 3.81 (m); 2.73 (m); 2.46 (m); 1.53(s).

[0259] Intermediate 16

[0260](+/−)-Z-Ethyl2-(5-chloro-2-iodoanilino)-4-(2-oxo-1-(4-tert-butoxycarbonylamino)phenyl-pyrrolidin-3-ylidene)butanoate

[0261] A solution of intermediate 15 (2.6 g) in dry DMF (100 ml) andtributylphosphine was refluxed at 110° C. under a nitrogen atmospherefor 4 h, until reaction completion (TLC). The mixture was concentratedin vacuum to give the crude1-(4-tert-butoxycarbonylamino)phenyl-2-oxo-pyrrolidin-3-yl-tributylphosphoniumbromide (1.75 g) which was dissolved in dry CH₃CN (100 ml) was cooled at−30° C. and stirred under a nitrogen atmosphere, then DBU (0.44 ml) andintermediate 2 (1.0 g) were added. The mixture was stirred for 1 h thenwas poured into a saturated solution of NH₄Cl (200 ml) extracted with EA(3×150 ml) and the organic extracts were washed with brine (200 ml),dried and concentrated in vacuum to give a yellow oil which was purifiedby flash chromatography (eluting with CH/EA 80:20) to give the titlecompound (0.085 g) as a white solid. T.l.c. CH-EA (7:3), R_(f)=0.23 IR:1727 and 1695 (C═O) cm⁻¹. ¹H-NMR: 7.64 (d); 7.53 (d); 7.38 (d); 6.48(d); 6.47 (sa); 6.45 (dd); 5.97(m); 5.02(d); 4.23 (m); 4.14 (m); 3.8(t);3.6 (m); 3.3 (m); 2.85 (m); 1.53(s); 1.27(t).

[0262] Intermediate 17

[0263] (±)-Z-Benzyl2-(5-chloro-2-iodoanilino)-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)butanoate

[0264] To a solution of the derivativeN-(phenylaminocarbonyl)α-phosphonoglycine-trimethyl ester (0.1 g) inacetonitrile (10 ml) DBU (0.1 ml) was added and after 10 min a solutionof the (+/−)-2-(5-Chloro-2-iodo-phenylamino)-4-oxo-butyric acid benzylester (0.1 g) in acetonitrile (2 ml). The reaction mixture was stirredfor 1½ hr, then diluted with ethyl acetate and washed with a 1N solutionof HCl and brine. The organic phase was dried and concentrated to givethe crude product which was purified by flash column chromatography toobtain the title compound (0.065 g)

[0265] NMR (DMSO) δ (ppm) 10.80 (s, 1H), 7.65 (d, 1H), 7.7-7.3 (m, 10H),6.75 (d, 1H), 6.55 (dd, 1H), 5.70 (t, 1H), 5.20 (s, 2H), 5.07 (d, 1H),4.72 (m, 1H), 2.86 (t, 2H

[0266] IR (Nujol) (cm⁻¹) 3339, 3160, 1768, 1721, 1691

[0267] Intermediate 18

[0268] (±)-Benzyl7-chloro-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0269] To a solution of intermediate 17 (0.065 g) in DMF (5 ml)Pd(PPh₃)₄ (16 mg) and TEA (0.05 ml) were added and the resultingsolution was heated to 110° C. for 1 h. The crude solution was pouredinto ethyl acetate and washed with a 1N solution of HCl and brine. Theorganic phase was dried and concentrated to give the crude product whichwas purified by flash column chromatography to obtain the title compound(0.015 g) as yellow powder.

[0270] m.p.>220° C.

[0271] NMR (DMSO) δ (ppm) 10.5 (s, 1H), 7.5-7.2 (m, 11H), 7.16 (bd, 1H),6.75 (d, 1H), 6.58 (dd, 1H), 5.2-5.01 (dd, 2H), 4.40 (m, 1H), 4.25 (dd,1H), 2.83 (dd, 1H).

[0272] IR (Nujol) (cm⁻¹) 3378, 1752, 1728, 1704

[0273] Intermediate 19

[0274] 2-[2-(5-Chloro-2-iodo-phenylimino)-acetoxy]-1-(R)-methyl-aceticAcid Isobutyl Ester

[0275] To a solution of acrylic acid1-isobutoxycarbonyl-1-(R)-methyl-methyl ester (3.7 g) in THF/H₂O OsO4 4%in H20 (4 ml) was added. The black suspension was then treated withNalO4 (10.5 g) by portions. After 5 hrs, the solution was taken up withethyl acetate (2×50 ml) and washed with water (2×50 ml). The organicphase evaporated under vacuum and the crude mixture was purified byflash chromatography (CH/EA 1:1) to afford2-(2-Oxo-acetoxy)-1-(R)-methyl-acetic acid isobutyl ester as colourlessoil (3 g). 24.8 g of 2-(2-Oxo-acetoxy)-1-(R)-methyl-acetic acid isobutylester was dissolved in toluene (1000 ml) and refluxed in a Dean-Starkapparatus for 2 hrs. After cooling to room temperature,5-chloro-2-iodoaniline (22 g) was added, and the solution refluxed inthe presence of MgSO₄ for 3 hrs. The clear solution was cooled, filteredthrough cotton to eliminate the MgSO₄, concentrated to dryness to obtainthe title compound (38 g) as a yellow oil.

[0276] NMR (CDCl₃) δ (ppm) 7.83 (1H, d), 7.79 (s 1H), 7.02(dd, 1H), 6.96(d, 1H), 5.373 (q 1H), 4.00 (m, 2H), 2.00 (m, 1H), 1.67 (d, 3H), 0.96(2d, 6H)

[0277] IR (CDCl3): 1749, 1730

[0278] Intermediate 20

[0279] 2-(5-Chloro-2-iodo-phenylamino)-4-oxo-butyric Acid1-isobutoxycarbonyl-1(R)-methyl-methyl Ester (20a and 20b)

[0280] A solution of intermediate 19 (38 g) in toluene (1 ml) was cooledto −20° C. and Yb(OTf)3 (16.5 g) was added and, after a few minutes,vinyloxy trimethylsilane (12.5 g) dissolved in toluene (50 ml) was addeddrop-wise. The bath was removed and the reaction allowed to stir for 2hrs. The crude mixture was taken up with ethyl acetate (500 ml) and theorganic phase was washed with a saturated solution of ammonium chloride(300 ml) and evaporated. Then, the mixture was purified by columnchromatography (cyclohexanelethyl acetate 85/15) to afford the titlecompounds 20a (14 g) and 20b (4 g) as colourless oils.

[0281] Intermediate 20a

[0282] NMR (CDCl₃) δ (ppm) 9.85 (s, 1H), 7.57 (d, 1H), 6.58 (d, 1H),6.51 (dd, 1H), 5.19 (m, 1H), 4.97 (d, 1H), 4.63 (m, 1H), 3.93 (m, 2H),3.24-3.04 (m, 2 H), 1.94 (m, 1H), 1.53 (d, 3H), 0.93 (dt, 3H); 0.91 (d,3H).

[0283] IR (CDCl3) (cm⁻¹) 1742, 1740

[0284] Intermediate 20b

[0285] NMR (CDCl₃) δ (ppm) 9.81 (s, 1H), 7.57 (d, 1H), 6.60 (d, 1H),6.52 (dd, 1H), 5.17 (m, 1H), 4.95 (d, 1H), 4.57 (m, 1H), 3.92 (m, 2H),3.11 (m, 2H); 1.92 (m, 1H); 1.50 (d, 3H); 0.90 (d, 6H).

[0286] IR (CDCl3) (cm⁻¹) 3375, 1734

[0287] Intermediate 21

[0288](E)-2-(5-Chloro-2-iodo-phenylamino)-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-butyricacid 1-isobutoxycarbonyl-1-(R) methyl-methyl Ester

[0289] To a solution of intermediate 3 (14.45 g) in acetonitrile (200ml) DBU (4.43 ml) was added at room temperature and the mixture wasstirred for 10 min. The mixture was then cooled at −25° C. andintermediate 31a (12.98 g) in 60 ml of CH3CN was added drop-wise in 15min. Then the reaction was stirred at this temperature for 2 h. Then themixture was taken up with ethyl acetate (100 ml) and the organic phasewashed with a saturated solution of NH4Cl (150 ml), and HCl 2% (200 ml)and brine (2×200 ml). The solution was then dried and concentrated.Final purification by column chromatography (cyclohexanelethylacetate/CH2C/2 7/0.5/2.5) afforded the title compound (11.04) as a whitefoam.

[0290] NMR (CDCl₃) δ (ppm) 7.73 (m, 2H), 7.56 (d, 1H), 7.38 (t, 2H),7.16 (m, 1H), 6.67 (m, 1H), 6.50(dd, 1H), 6.49 (s, 1H), 5.20 (q, 1H),4.81 (d, 1H), 4.33 (m, 1H), 3.94 (d, 2H), 3.88 (t, 2H), 3.0-2.74 (m,4H), 1.94 (m, 1H), 1.57 (d, 3H); 0.91 (d, 6H).

[0291] IR (CDCl3); 1696, 1670 cm−1

[0292] Intermediate 22

[0293]7-Chloro-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-quinoline-2-carboxylicAcid, [1R)-methyl-1-isobutoxycarbonyl]-methyl Ester (Diastereoisomer A)

[0294] To a solution of intermediate 21 (9.55 g) in toluene (130 ml),Pd(PPh₃)₄ (3.52 g) and triethylamine (5.1 ml) were added in portions andthe mixture was heated to 110° C. for 3.5 hr. The crude solution wastaken up with ethyl acetate (600 ml) and washed with NH4Cl and brine,dried and evaporated. Purification by column chromatography(cyclohexaneldichloromethane/ethyl acetate 6.5/3/0.5) afforded the titlecompound (6.08 g) as a yellow foam.

[0295] NMR (DMSO) δ (ppm) 7.71 (d, 2H), 7.35 (t, 2H), 7.20 (d, 1H), 7.11(t, 1H), 7.00 (s,1H), 6.74 (d, 1H), 6.57 (dd, 1H), 4.89 (q, 1H), 4.24(m, 2H), 3.84-3.60 (m, 4H), 3.2-2.8 (m, 3H), 1.70 (m, 1H), 1.24 (d, 3H);0.73 (d, 6H).

[0296] IR (nujol): 3377, 1746, 1670

[0297] Intermediate 23

[0298]7-Chloro-4-(2-oxo-1-phenyl-2,5-dihydro-1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylicAcid, [1-(R)-methyl-1-isobutoxycarbonyl]-methyl Ester

[0299] To a solution of intermediate 22 (3.67 g) in DMF (50 ml)Pd(PPh₃)₄ (0.340 g) and triethylamine (2 ml) were added and the mixturewas heated to 110° C. for 2 hrs. The crude solution was taken up withethyl acetate (2×200 ml) and washed with NH4Cl and brine, dried andevaporated. Final purification by column chromatography(cyclohexane/dichloromethane/ethyl acetate 6.5/3/0.5) afforded the titlecompound (1.289 g) as a yellow foam.

[0300] NMR (DMSO) δ (ppm) 7.79 (d, 2H), 7.38 (t, 2H), 7.11 (t, 1H), 6.79(d, 1H), 6.57 (d, 1H), 6.74 (d, 1H); 6.47 (dd, 1H); 6.47 (m, 1H); 5.10(q, 1H); 4.49 (m, 2H); 4.06 (m, 1H); 3.92-3.82 (m, 3H); 2.45 (m, 1H);2.019 (m, 1H); 1.84 (m, 1H); 1.42 (d, 3H); 0.84 (d, 6H).

[0301] IR (nujol): 3375, 1749, 1683.

[0302] Intermediate 24

[0303] 2-(3,5-Dichloro-2-iodo-phenylamino)-4-oxo-butyric Acid1-n-butoxycarbonyl-1(S)-methyl-methyl Ester (24a and 24b)

[0304] To a solution of intermediate Acrylic acid1-n-butoxycarbonyl-1-(S)-methyl-methyl ester (4.9 g) in THF/H₂O (100 ml,2/1) OsO4 4% in H20 (2.8 g) was added. The black suspension was thentreated with NalO4 (13 g) by portions. After 5 hrs, the solution wastaken up with ethyl acetate (2×50 ml) and washed with water (2×50 ml).The organic phase evaporated under vacuum and the crude mixture waspurified by flash chromatography (CH/EA 1:1) to afford the2-(2-oxo-acetoxy)-1-(S)-methyl-acetic acid n-butyl ester as a colourlessoil (4.85 g). (2.5 g) of which was dissolved in toluene (200 ml) andrefluxed in a Dean-Stark apparatus for 2 hrs. After cooling to roomtemperature, 3,5-dichloro-2-iodoaniline (2.46 g) was added, and thesolution refluxed in the presence of MgSO₄ for 3 hrs. The clear solutionwas cooled, filtered through cotton to eliminate the MgSO₄, concentratedto dryness to obtain(2-[2-(5-chloro-2-iodo-phenylimino)acetoxy]-1-(S)-methyl-acetic acid nbutyl ester (4 g,) as a yellow oil.

[0305] A solution of such a yellow oil in CH3CN (70 ml) was cooled to−30° C. and Yb(OTf)3 (2.1 g) was added and, after a few minutes,vinyloxy trimethylsilane (1.1 g) dissolved in CH3CN (20 ml) was added,drop-wise. The reaction was stirred for 10 min. The crude mixture wastaken up with ethyl acetate (500 ml) and the organic phase was washedwith a saturated solution of ammonium chloride (2×50 ml) and evaporated.Then, the mixture was purified by column chromatography(cyclohexanelethyl acetate 90/10) to afford the title compounds 24a (1.4g) and 24b (0.7 g) as colourless oils.

[0306] Intermediate 24a

[0307] NMR (CDCl₃) δ (ppm) 9.84 (t, 1H), 6.92 (d, 1H); 6.45 (d, 1H);5.33 (da, 1H); 5.17 (q, 1H); 4.60 (m, 1H); 4.14 (m, 2H); 3.34-3.06 (m,2H); 1.6 (m, 2H); 1.52 (d, 3H); 1.37 (m, 2H); 0.93 (t, 3H).

[0308] IR (CDCl3) (cm⁻¹) 3370, 1742

[0309] Intermediate 24b

[0310] NMR (CDCl₃) δ (ppm) 9.80 (s, 1H), 6.92 (d, 1H); 6.47 (d, 1H); 5.3(da, 1H); 5.15 (q, 1H); 4.55 (m, 1H); 4.14 (m, 2H); 3.13 (m, 2H); 1.57(m, 2H); 1.49 (d, 3H); 1.34 (m, 2H); 0.91 (t, 3H).

[0311] IR (CDCl3) (cm⁻¹) 3370, 1744.

[0312] Intermediate 25

[0313](E)-2-(3,5-Dichloro-2-iodo-phenylamino)-4-(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-butyricacid 1-n-butoxycarbonyl-1-(S) methyl-methyl Ester (Diastereoisomer A)

[0314] To a solution of intermediate 2a (0.893) in acetonitrile (20 ml)DBU (0.25 ml) was added at room temperature and the mixture was stirredfor 10 min. The mixture was then cooled at −25° C. and intermediate 6b(0.8 g) in 10 ml of CH3CN was added drop-wise in 15 min. Then thereaction was stirred at this temperature for 30 min. Then the mixturewas taken up with ethyl acetate (50 ml) and the organic phase washedwith a saturated solution of NH4Cl (50 ml), and HCl 2% (10 ml) and brine(2×20 ml). The solution was then dried and concentrated. Finalpurification by column chromatography (cyclohexanelethyl acetate 8/2)afforded the title product (0.734 g) as a white foam.

[0315] NMR (CDCl₃) δ (ppm) 7.72 (d, 2H), 7.39 (t, 2H), 7.17 (t, 1H);6.92 (d, 1H); 6.60 (m, 1H); 6.43 (d, 1H); 5.16 (q, 1H); 5.14 (d, 1H);4.34 (d, 1H); 4.15 (m, 2H); 3.89 (t, 2H); 2.75-2.4 (m, 4H); 1.60 (m,2H); 1.53 (d, 3H); 1.34 (m, 2H); 0.91 (t, 3H).

[0316] IR (CDCl3); 3377, 1744, 1697, 1672 cm−1

[0317] Intermediate 26

[0318]5,7-Dichloro-4-(2-oxo-1-phenyl-2,5-dihydro-1H-pyrrol-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylicAcid, [1(S)-methyl-1-n-butoxycarbonyl]-methyl Ester(26a)5,7-Dichloro-4(2-oxo-1-phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydroquinoline-2-carboxylicAcid, [1-(S)-methyl-1-n-butoxycarbonyl]-methyl Ester (26b)

[0319] To a solution of intermediate 25 (0.734 g) in DMF (20 ml)Pd(OAc)₂ (0.110 g) and triethylamine (0.37 ml) were added in portions,and the mixture was heated to 120° C. for 3 hr. The crude solution wastaken up with ethyl acetate (1000 ml) and washed with NH4Cl and brine,dried and evaporated. Final purification by column chromatography(cyclohexaneldichloromethane/ethyl acetate 7/2.5/0.5) afforded the titlecompound 26a (0.35 g) and 26b (0.06 g) as a yellow foam.

[0320] Intermediate 26a

[0321] NMR (DMSO) δ (ppm) 7.80 (d, 2H); 7.38 (t, 2H); 7.11 (t, 1H); 6.89(d, 1H); 6.83 (s, 1H); 6.68 (d, 1H); 6.47 (d, 1H); 5.07 (q, 1H); 4.48(m, 2H); 4.11 (m, 1H); 4.06 (t, 2H); 3.8 (dd, 1H); 2.3-1.8 (m, 2H); 1.52(m, 2H); 1.40 (d, 3H); 1.54 (m, 2H); 1.3 (m, 2H); 0.84 (t, 3H).

[0322] IR (nujol): 3374, 1740, 1683 cm⁻¹

[0323] Intermediate 26b

[0324] NMR (DMSO) δ (ppm) 7.69 (d, 2H); 7.39 (t, 2H); 7.33 (d, 1H); 7.15(t, 1H); 6.71 (d, 1H); 6.62 (d, 1H); 4.72 (d, 1H); 4.40 (q, 1H); 4.40(m, 1H); 3.94 (t, 2H); 3.76 (t, 1H); 3.60 (q, 1 H); 3.12 (m, 1H); 2.35(m, 1H); 2.21 (dd, 1H); 1.42 (m, 2H); 1.21 (m, 2H); 0.97 (d, 3H); 0.82(t, 3H).

[0325] IR (nujol): 3377, 1746, 1684, 1594cm⁻¹

EXAMPLE 1

[0326] (±)-Sodium7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0327] To a solution of example 31a (540 mg) in IMS (5% methanol inabsolute ethanol, 7 ml) NaOH (1N, 1.4 ml) was added and stirringcontinued for 2 hrs. The resulting solution was dried on the rotaryevaporator and the resulting solid was triturated with diethyl ether.After filtration and drying the title compound (440 mg) was obtained asan off-white solid.

[0328] m.p.>200° C.

[0329] NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.80(d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (dd, 1H), 5.71 (s, 1H), 4.42(m, 2H), 3.77 (m, 1H), 3.13 (m, 1H), 2.29 (m, 1H), 1.44 (m, 1H).

[0330] IR (Nujol) (cm⁻¹) 1672, 1600.

EXAMPLE 2

[0331] (−)-Sodium7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0332] To a solution of intermediate 8a (690 mg) in THF/H₂O (1/1) (14ml) LiOH (65 mg) was added and stirring continued for 1 h. The resultingsolution was concentrated to dryness, taken up with ethyl acetate and 1NHCl was added. After vigorous stirring, the organic phase was separated,washed with water and brine and concentrated. The resulting solid wasdissolved in THF (15 ml) and treated with sodium ethylhexanoate (232 mg)for 30 min. After drying, the resulting solid was triturated with hotdiethyl ether and filtered, to afford the title compound (160 mg) as awhite solid.

[0333] e.e.=99%

[0334] [α]_(D)=−102.3° (c=0.09% w/v in DMSO)

[0335] m.p.>200° C.

[0336] NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.80(d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (dd, 1H), 5.71 (s, 1H), 4.42(m, 2H), 3.77 (m, 1H), 3.13 (m, 1H), 2.29 (m, 1H), 1.44 (m, 1H).

[0337] IR (Nujol) (cm⁻¹) 1672, 1600.

EXAMPLE 3

[0338] (±)-Ethyl7-chloro-4(1-phenyl-Δ³-5,6-dihydro-pyridin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate(3a)

[0339] (±)-Ethyl7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate(3b)

[0340] To a solution of intermediate 9 (0.2 g) in DMF (5 ml) Pd(PPh₃)₄(41 mg) and TEA (0.1 ml) were added and the resulting solution washeated to 110° C. for 2 hrs. The crude solution was poured into ethylacetate and washed with a 1N solution of HCl and brine. The organicphase was dried and concentrated to give the crude product which waspurified by flash column chromatography to obtain the title compound 3a(0.085 g) as a white powder.

[0341] m.p.=131-133° C.

[0342] NMR (DMSO) δ (ppm) 7.4-7.3 (m, 4H), 7.20 (t, 1H), 6.78 (d, 1H),6.75 (d, 1H), 6.48 (dd, 1 H), 6.34 (bs, 1H), 5.99 (t, 1H), 4.13 (m, 2H),3.97 (t, 1H), 3.93 (dd, 1H), 3.77 (m, 2H), 2.45 (m, 2H), 2.15 (m, 1H),1.85 (m, 1H), 1.19 (t, 3H).

[0343] IR (Nujol) (cm⁻¹) 3392, 1723, 1659 and the title compound 3b(0.055 g) as pale yellow powder.

[0344] m.p.=99-101° C.

[0345] NMR (DMSO) δ (ppm) 7.4-7.2 (m, 5H), 7.01 (d, 1H), 6.93 (d, 1H),6.68 (d, 1H), 6.52 (dd, 1H), 4.20 (m, 1H), 4.16-3.96 (m, 2H), 3.74-3.60,3.40 (m, 2H), 2.9-2.5 (m, 3H), 2.0-1.6 (m, 2H), 1.14 (t, 3H).

EXAMPLE 4

[0346] (±)-Ethyl7-chloro-4-(1-pyridin-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate(4a)

[0347] (±)-Ethyl7-chloro-4-(2oxo-1-(pyridin-3-yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate(4b)

[0348] To a solution of example 3 (0.47 g) in DMF (20 ml) Pd(PPh₃)₄ (100mg) and TEA (0.38 ml) were added and the resulting solution was heatedto 110° C. for 1½ h. The crude solution was poured into ethyl acetateand washed with a saturated solution of NH₄Cl and brine. The organicphase was dried and concentrated to give the crude mixture which wasdissolved in ethyl acetate (2 ml) and treated with petroleum (2 ml) thesolid was filtered to give the title compound 4a (0.08 g) as a whitepowder.

[0349] m.p.=132-134° C.

[0350] NMR (DMSO) δ (ppm) 8.99 (d, 1H), 8.32 (dd, 1H), 8.21 (m, 1H),7.41 (dd, 1H), 6.80 (d, 1H), 6.77 (m, 1H), 6.75 (d, 1H), 6.47 (dd, 1H),6.45 (m, 1H), 4.56 (m, 1H), 4.50 (m, 1H), 4.2-4.02 (m, 2H), 3.99 (m,1H), 3.81 (t, 1H), 2.31 (m, 1H), 1.97 (m, 1H), 1.18 (t, 3H).

[0351] IR (Nujol) (cm⁻¹) 3391, 1728, 1679

[0352] The mother liquor was purified by flash chromatography to obtaina product which was triturated in cyclohexane to obtain title compound4b (0.067 g, yellow powder).

[0353] NMR (DMSO) δ (ppm) 8.94 (d, 1H), 8.34 (dd, 1H), 8.14 (m, 1H),7.41 (dd, 1H), 7.19 (d, 1H), 7.00 (d, 1H), 6.73 (d, 1H), 6.56 (dd, 1H),4.27 (m, 1H), 4.20 (m, 1H), 4.00 (m, 1H), 3.89 (m, 1H), 3.85 (m, 1H),3.72 (m, 1H), 3.21 (m, 1H), 2.93 (m, 1H), 2.84 (m, 1H), 0.90 (t, 3H).

[0354] IR (Nujol) (cm⁻¹) 3366, 1734, 1676.

EXAMPLE 5

[0355] (±)-Ethyl5,7-dichloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0356] To a solution of intermediate 11 a (0.430 g) in DMF (10 ml)Pd(OAc)₂ (11.6 mg) and TEA (0.12 ml) were added and the resultingsolution was heated to 130° C. for 2 h. The crude solution was pouredinto 20 ml of ethyl acetate and washed first with a saturated solutionof NH₄Cl (2×15 ml), then with water and brine. The organic phase wasdried with Na₂SO₄ and concentrated to give the crude product.Purification by column chromatography (cyclohexane/dichloromethane/ethylacetate 60/30/10) gave the title compound (0.087 g) as an off-whitesolid.

[0357] NMR (DMSO) δ (ppm) 7.81 (m, 2H), 7.40 (m, 2H), 7.13 (m, 1H), 6.91(d, 1H), 6.75 (Sa, 1H), 6.68 (d, 1H), 6.45 (m, 1H), 4.46 (m, 2H),4.17-4.10 (m, 3H), 3.79 (dd, 1H), 2.31 (m, 1H), 1.84 (m, 1H), 1.20 (t,3H)

[0358] IR (Nujol) (cm⁻¹) 3390, 1724, 1678.

EXAMPLE 6

[0359] (+/−)-Ethyl7-chloro-4-(1-(4-tert-butoxycarbonylamino)-phenyl-Δ3-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0360] A solution of intermediate 16 (0.085 g) in dry DMF (5ml) wasstirred in the presence of TEA (0.018 ml) and Pd(OAc)₂ (0.0015 g) undera nitrogen atmosphere at 110° C. for 1 h. The mixture was diluted with asaturated aqueous ammonium chloride solution (100 ml), and EA (100 ml);the organic layer was washed with brine (100 ml), dried and concentratedin vacuum. The crude mixture was purified by flash chromatography(eluting with CH/EA 8:2) to give the title compound as a yellow solid(0.050 g).

[0361] T.l.c. CH-EA (8:2) R_(f)=0.30. ¹H-NMR:9.30 (sa); 7.64 (d); 7.43(d); 6.80 (d); 6.75 (d); 6.63 (m); 6.46 (dd); 6.42 (sa); 4.40 (m); 4.13(m); 3.92 (m); 3.78 (m); 2.31 (m); 1.94 (m); 1.45 (s); 1.18(t).

EXAMPLE 7

[0362] (+/−)-Ethyl7-chloro-4-(1-(4-amino)-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0363] To a solution of example 6 (0.070 g) in ethyl acetate (35 ml) HClconc. (2.0 ml) was added. The mixture was stirred a r.t. under nitrogenatmosphere for 1 h. The mixture was poured into a saturated aqueoussolution of NaHCO₃ (100 ml) and extracted with EA (200 ml); the organiclayer was dried and concentrated in vacuum. The crude mixture waspurified by flash chromatography (eluting with CH/EA 1:1) to give thetitle compound as a yellow solid (0.043 g).

[0364] T.l.c. EA R_(f)=0.289. IR:3388 (NH), 3161(NH₂), 1718 and 1670(C═O) cm⁻¹.

[0365]¹H-NMR, 7.36 (d); 6.80 (d); 6.75 (d); 6.56 (m); 6.47 (dd);6.41(sa); 4.97(m); 4.32 (m); 4.14 (m); 3.91 (m); 3.77(m); 2.31 (m); 1.94(m); 1.19(t).

EXAMPLE 8

[0366] (+/−)-Ethyl7-chloro-4-(1-(4-acetylamino)-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0367] To a solution of example 7 (0.030 g) in pyridine dry (1 ml) Ac₂O(0.012 ml) was added. The mixture was stirred at r.t. under nitrogenatmosphere for 30 minutes. The mixture was poured into a saturatedaqueous solution of NH₄Cl (50 ml) and extracted with EA (50 ml), theorganic layer was dried and concentrated in vacuum. The crude mixturewas triturated with EA to give the title compound as a white solid(0.025 g)

[0368] T.l.c. CH/EA (1:1) R_(f)=0.33. IR:3401(NH), 1730, 1675, 1651(C═O) cm⁻¹. d

[0369]¹H-NMR:9.9 (s); 7.69 (d); 7.56 (d); 6.80 (d); 6.75 (d); 665 (m);6.47 (dd); 6.43 (sa); 4.54.37 (m); 4.13 (m); 3.93 (m); 3.79 (m);2.3-1.94 (m); 2.03 (s); 1.19 (t).

EXAMPLE 9

[0370] (+/−)-Ethyl7-chloro-4-(1-(4-methanesulfonylamino)-phenyl-Δ³-pyrrolin-2one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0371] To a solution of example 7 (0.040 g) in CH₂Cl₂ dry (10 ml) DIPEA(0.021 ml) and CH₃SO₂Cl (0.008 ml) were added. The mixture was stirredat r.t. under nitrogen atmosphere for 1 h. The mixture was poured onto asaturated aqueous solution of NH₄Cl (50 ml) and extracted with EA (50ml), the organic layer was dried and concentrated in vacuum. The crudemixture was purified by flash chromatography (eluting with CH/EA (1:1)to give the title compound as a yellow solid (0.027 g).

[0372] T.l.c. CH/EA (1:1) R_(f)=0.63. IR:3394(NH, 1726, 1680, 1635(C═O), (C═C) cm⁻¹.

[0373]¹H-NMR:7.89 (d); 7.52 (d); 6.81 (d); 6.76 (d); 6.76 (s); 6.47(dd); 6.45 (sa); 4.52 (m); 4.13 (m); 3.94 (m); 3.81(m); 3.51 (s);2.3-1.97 (m); 1.19 (t)

EXAMPLE 10

[0374] (+)-Ethyl 7-chloro-4-(2-oxo-1-((4-tert-butoxycarbonylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0375] A solution of intermediate 16 (1.02 g) in dry DMF (100 ml) wasstirred in the presence of TEA (0.018 ml) and Pd(PPh₃)₄ (0.184 g) undera nitrogen atmosphere at 110° C. for 2 h until reaction completion(TLC). The mixture was diluted with a saturated aqueous ammoniumchloride solution (100 ml) and EA (200 ml); the organic layer was washedwith brine (200 ml), dried and concentrated in vacuum. The crude mixturewas purified by flash chromatography (eluting with CH/DCM/EA 5:4:1) togive the title compound (280 mg).

[0376] IR:3350 (NH), 1718 and 1670 (C═O) cm⁻¹. ¹H-NMR: 9.32 (sa); 759(d); 7.43 (d); 7.17 (d); 6.94 (d); 6.72 (m); 6.55 (dd); 4.26 (dd);4.19(m); 4.04-3.88 (m); 3.8-3.6 (m); 3.18(m); 2.94-2.86 (m); 1.46 (s);0.92 (t).

EXAMPLE 11

[0377] (+)-Ethyl7-chloro-4-(2-oxo-1-(4-amino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0378] To a solution of example 10 (0.280 g) in ethyl acetate (100 ml)HCl conc. (9.5 ml) was added. The mixture was stirred a r.t. undernitrogen atmosphere for 1 h until reaction completion (Tlc). The mixturewas poured onto a saturated aqueous solution of NaHCO₃ (100 ml) andextracted with EA (200 ml); the organic layer was dried and concentratedin vacuum. The crude mixture was triturated with CH/EA 1:1 to give thetitle compound as a yellow solid (0.191 g).

[0379] T.l.c. EA R_(f)=0.33. IR:3464-3406(NH), 3364(NH₂), 1730, 1658 and1633 (C═O) cm⁻¹.

[0380]¹H-NMR: 7.31 (d);7.16 (d); 6.91 (da); 6.71 (d); 655 (d); 6.54(dd); 5.01(s); 4.26 (dd); 4.17 (m);4.04-3.9 (m); 3.74-3.54(m); 3.14 (m);2.87 (m);0.96(t).

EXAMPLE 12

[0381] (+)-Ethyl7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0382] To a solution of intermediate 19 dry pyridine (1 ml) Ac₂O (0.010ml) was added. The mixture was stirred a r.t. under nitrogen atmospherefor 30 minutes. The mixture was poured onto a saturated aqueous solutionof NH₄Cl (50 ml) and extracted with EA (50 ml), the organic layer wasdried and concentrated in vacuum. The crude mixture was triturated withEA to give the title compound as a yellow solid (0.027 g).

[0383] T.l.c. CH/EA (1:1) R_(f)=0.63 IR:3396-3325(NH), 1724-1685 (C═O)cm⁻¹.

[0384]¹H-NMR:9.92 (s); 7.62 (d); 7.55 (d);7.16 (d); 6.95 (da); 6.71 (d);655 (dd); 5.01(s); 4.25 (dd); 4.18 (m);4.1-3.85 (m); 3.77(m); 3.64 (m);3.18 (m); 2.88 (m); 2.01 (s); 0.91 (t).

EXAMPLE 13

[0385] (+)-Ethyl7-chloro-4-(2-oxo-1-((4-methanesulfonyl-amino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0386] To a solution of example 12 (0.040 g) in dry CH₂Cl₂ (10 ml) DIPEA(0.021 ml) and CH₃SO₂Cl (0.008 ml) were added. The mixture was stirred ar.t. under nitrogen atmosphere for 1 h (Tlc). The mixture was pouredonto a saturated aqueous solution of NH₄Cl (50 ml) and extracted with EA(50 ml), the organic layer was dried and concentrated in vacuum. Thecrude mixture was crystallised with CH/EA (1:1) to give the titlecompound as a yellow solid (0.023 g). T.l.c. CH/EA (1:1) R_(f)=0.63.

[0387] IR:3384(NH), 1734, 1683 (C═O), 1600 (C═C) cm⁻¹.

[0388]¹ H-NMR:7.83 (d); 7.53 (d); 7.21 (d);7.00 (d); 6.75 (d); 6.57(dd); 4.2-4.3 (m); 4.01 (m); 3.93 (m); 3.87 (m); 3.73 (m);3.52(s); 3.22(m); 3.0-2.9 (m); 0.95 (t).

EXAMPLE 14

[0389] (±)-Sodium7-chloro-4-(1-(3-pyridin)-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0390] To a solution of example 4a (70 mg) in IMS (5% of methanol inethanol) (10 ml) a 1N solution of NaOH (0.18 ml) was added and reactionmixture was stirred for 1½ hr. The solvent was evaporated and the crudeproduct was first triturated in methanol/ethyl acetate 05 ml/2 ml thenin isopropyl alcohol (3 ml) to yield the title compound (40 mg) as apale yellow solid.

[0391] m.p.>220° C.

[0392] NMR (DMSO) δ (ppm) 8.98 (d, 1H), 8.31 (dd, 1H), 8.21 (m, 1H),7.41 (m, 1H), 6.79 (d, 1H), 6.72 (d, 1H), 6.42 (d, 1H), 6.33 (dd, 1H),5.71 (s, 1H), 4.50 (m, 1H), 4.44 (m, 1H), 3.76 (m, 1H), 3.11 (m, 1H),2.27 (m, 1H), 1.43 (m, 1H).

[0393] IR (Nujol) (cm⁻¹) 3300, 1684.

EXAMPLE 15

[0394] (±)-Sodium7-chloro-4-(1-phenyl-Δ³-5,6-dihydro-pyridin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0395] To a solution of example 3a (80 mg) in IMS (5% of methanol inethanol) (6 ml) a 0.1N solution of NaOH (2.9 ml) was added and reactionmixture was stirred for 1 hr. The solution was poured into ethyl acetateand washed with a 1N solution of HCl and brine. The organic phase wasdried with Na₂SO₄ and concentrated to give the crude acid compound. Thelatter was suspended in ethyl acetate (2 ml) and sodium 2-ethylhexanoate(35 mg) was added obtaining a solution. Diethyl ether (4 ml) andpetroleum (3 ml) was added to precipitate the title compound (42 mg) asa white solid.

[0396] m.p.>163-166° C.

[0397] NMR (DMSO) δ (ppm) 7.4-7.34 (m, 4H), 7.19 (m, 1H), 6.72 (d, 1H),6.67 (d, 1H), 6.32 (d, 1H), 6.32 (dd, 1H), 5.71 (t, 1H), 5.64 (s, 1H),3.96 (m, 1H), 3.8-3.65 (m, 2H), 3.17 (dd, 1H), 2.4 (m, 2H), 2.08 (1H),1.3 (m, 1H)

[0398] IR (Nujol) (cm⁻¹) 3373, 1658, 1653

EXAMPLE 16

[0399] (±)-Sodium5,7-dichloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0400] To a solution of example 5 (87 mg) in IMS (5% methanol inabsolute ethanol, 5 ml) NaOH (1N, 0.22 ml) was added and stirringcontinued for. 3 hrs. The resulting solution was dried on the rotaryevaporator and the resulting solid was triturated with diethyl ether.After filtration and drying the title compound (78 mg) was obtained asan off-white solid.

[0401] NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.38 (t, 2H), 7.10 (t, 1H), 6.82(d, 1H), 6.46 (d, 1H), 6.37 (s, 1H), 6.11 (s, 1H), 4.42 (s, 2H), 3.98(d, 1H), 3.05 (dd, 1H), 2.24 (dd, 1 H), 1.34 (m, 1H).

[0402] IR (Nujol) (cm⁻¹) 3385, 1663, 1591, 1555

EXAMPLE 17

[0403](+)Sodium-7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0404] Method A

[0405] To a solution of intermediate 13 (110 mg) in THF/H₂O (1/1) (3 ml)LiOH (11 mg) was added and stirring continued for 1 h. The resultingsolution was concentrated to dryness, taken up with ethyl acetate and 1NHCl was added. After vigorous stirring, the organic phase was separated,washed with water and brine and concentrated. The resulting solid wasdissolved in THF (15 ml) and treated with sodium ethylhexanoate (39 mg)for 30 min. After drying, the resulting solid was triturated with hotdiethyl ether and filtered, to afford the title compound (69 mg) as awhite solid.

[0406] e.r.=98%

[0407] [α]_(D)=92.5° (c=0.420% w/v in DMSO)

[0408] m.p.>200° C.

[0409] NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.11 (m, 1H), 6.80(d, 1H), 6.72 (d, 1H), 6.36 (d, 1H), 6.34 (dd, 1H), 5.71 (s, 1H), 4.42(m, 2H), 3.77 (m, 1H), 3.13 (m, 1H), 2.29 (m, 1H), 1.44 (m, 1H).

[0410] IR (Nujol) (cm⁻¹) 1672, 1600.

[0411] Method B

[0412] Starting from Example 28 using the procedure as described forExample 21 (Method B).

EXAMPLE 18

[0413](+/−)-7-chloro-4-(1-(4-acetylamino)-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicAcid

[0414] To a solution of example 8 (0.023 g) in IMS (5 ml) NaOH (0.150ml) was added and the mixture was stirred at r.t. for 1 h.

[0415] The mixture was poured onto a solution of HCl 6 N (50 ml) andextracted with EA (50 ml), the organic layer was washed with brine (30ml), dried and concentrated in vacuum. The crude mixture was trituratedwith Et₂O to give the title compound as a yellow solid (0.019g). T.l.c.EA R_(f)=0.2.

[0416] IR:3401(NH, OH), 1734, 1651 (C═O) cm⁻¹.

[0417] 1H-NMR:12.84 (bs); 9.9 (s); 7.69(d); 7.56 (d); 6.80 (d); 6.76(d);6.6 (d); 6.45 (dd);6.33 (sa); 4.42(m); 3.84-3.78(m); 3.70 (m); 2.3(m); 2.017 (s); 1.9 (m).

EXAMPLE 19(+/−)7-chloro-4-(1-(4-methanesulfonylamino)-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicAcid

[0418] To a solution of example 9 (0.027 g) in IMS (5 ml) was added NaOH(0.142 ml). The mixture was stirred a r.t. for 2 h.

[0419] The mixture was poured onto a solution of HCl 6N (50 ml) andextracted with EA (50 ml), the organic layer was washed with brine (30ml), dried and concentrated in vacuum. The crude mixture wascrystallized with CH/EA (1:1) to give the title compound as a yellowsolid (0.015 g). T.l.c. EA R_(f)=0.2. IR:3446(NH,), 1732-(C═O),1337-1154 (SO₂) cm⁻¹.

[0420]¹H-NMR:13-12 (broad); 9.61 (s); 7.75 (d); 7.21 (d); 6.80 (d); 6.76(d); 6.63 (dd); 6.46 (dd); 6.34 (dd); 4.43(m); 3.85-3.78 (m);2.93 (s);2.3 (m); 1.92 (m).

EXAMPLE 20

[0421] (±)-Sodium7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0422] To a solution of example 31b (540 mg) in IMS (5% methanol inabsolute ethanol, 7 ml) NaOH (1N, 1.4 ml) was added and stirringcontinued for 2 hrs. The resulting suspension was filtered and the solidwas washed with small portions of diethyl ether. After drying, the titlecompound (450 mg) was obtained as a yellow solid.

[0423] m.p.>200° C.

[0424] NMR (DMSO) δ (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H), 7.12(d, 1H), 6.77 (d, 1H), 6.38 (dd, 1H), 6.13 (bs, 1H), 4.48 (dd, 1H), 3.78(m, 2H), 3.2-3.4 (m, 2H), 2.90 (m, 1H), 1.98 (m, 1H)

EXAMPLE 21

[0425] (−)-Sodium7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0426] Method A

[0427] To a solution of intermediate 8b (790 mg) in THF/H₂O (1/1) (16ml) LiOH (73 mg) was added and stirring continued for 1 hr. Theresulting solution was concentrated to dryness, taken up with ethylacetate and 1N HCl was added. After vigorous stirring, the organic phasewas separated, washed with water and brine and concentrated. Theresulting solid was dissolved in THF (15 ml) and treated with sodiumethylhexanoate (265 mg) for 30 mins. After drying, the resulting solidwas triturated with hot ethyl acetate and filtered to afford the titlecompound (400 mg) as a yellow solid.

[0428] ee=88.8%

[0429] [α]_(D)−603.7° (c=0.316% w/v in DMSO)

[0430] m.p.>200° C.

[0431] NMR (DMSO) δ (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H), 7.12(d, 1H), 6.77 (d, 1H), 6.38 (dd, 1H), 6.13 (bs, 1H), 4.48 (dd, 1H), 3.78(m, 2H), 3.2-3.4 (m, 2H), 2.90 (m, 1H), 1.98 (m, 1H)

[0432] IR (Nujol) (cm⁻¹) 3425, 1666, 1592

[0433] Method B

[0434] To a solution of example 27 (3.18 g) in IMS (5% of methanol inethanol) (100 ml) a 1N solution of NaOH (8.64 ml) was added: the sodiumsalt precipitates after 5 min. To the resulting suspension diethyl etherwas added (50 ml) and the solid was filtered.

[0435] The solution was evaporated and the solid obtained was mixed tothe previous one and triturated with diethylether to afford the titlesodium salt (3.2 g) as yellow solid.

[0436] m.p.>220° C.

[0437] NMR (DMSO) δ (ppm) 7.74 (d, 2H), 7.37 (t, 2H), 7.11 (t, 1H); 7.11(d, 1H); 6.76 (d, 1H); 6.38 (dd, 1H); 6.11 (s, 1H); 4.48 (dd, 1H); 3.78(m, 2H); 3.4-3.2 (m, 2H); 2.9 (m, 1H); 1.95 (m, 1H).

[0438] IR (Nujol) (cm⁻¹) 3392, 1669.

[0439] [α]−603.7° (c=0.316% w/v in DMSO)

[0440] e.e.: 96%

[0441] Method C

[0442] 125 g of Aspergillus niger lipase (Amano AP12) were suspended in650 ml of 100 mM calcium chloride solution in a stirred reactor. Thesuspension was cooled to 15° C. 50 g of example 31b were then dissolvedin dimethyl sulphoxide (350 ml) and this solution added to the reactor.The reactor was then heated to 37° C. and the mixture stirred for 24hours.

[0443] The reactor temperature was then lowered to 20° C. and 1 liter of0.2M hydrochloric acid was slowly added to the reactor. The reactor wasthen emptied and 50 g of filter aid (Dicalite) were added to thereaction mixture. The mixture was then filtered and the filter cakewashed with water, before being dried. A 20 g sample of dried filtercake was dispersed in 390 ml of methyl t-butyl ether and 10 ml of 2Mhydrochloric acid were added. This was stirred for 3 hours and filtered,the filter cake was washed with 100 ml of methyl t-butyl ether. Theproduct was back extracted from the methyl t-butyl ether 500 into ml of0.05M sodium hydroxide solution. The aqueous layer was then separated,acidified with 6 ml of 5M hydrochloric acid and the product extractedinto 500 ml ethyl acetate. The ethyl acetate was removed by evaporationand the residue dissolved in IMS (80 ml). The title compound wasidentified in this solution by HPLC assay as follows:

[0444] 0.5 ml reaction mixture diluted into 2 mls DMSO and mixed todissolve. 5 ul of this further diluted ino 1 ml of mobile phase (70%acetonitrile in 20 mM Ammonium acetate pH 3.0), Column: Spherisorb C650×4.6 mm, Flow rate: 1 ml/min, Detection: uv adsorbance at 254 nm,Injection vol: 10 ul, Retention time: 0.8 min.

[0445] The solution was diluted to 96 ml with IMS and stirred while 10ml of 1 M sodium hydroxide were added drop-wise over 15 minutes. 40 mlof diethyl ether were added over 10 minutes and stirring continued for 1hour. The mixture was then placed in the fridge for 1 hour and theproduct filtered, washed with 50 ml of cold diethyl ether before beingdried overnight under vacuum to obtain the title compound (3.3 g). HPLCanalyses: the title compound was dissolved in DMSO at 1 mg/ml. 10 ul ofthis diluted into 990 ul of mobile phase.

[0446] Column: Phenomenex Luna Phenyl hexyl 150×4.6 mm, Injection vol:50 ul, Retention time: 3.4 min.

EXAMPLE 22

[0447] (±)-Sodium7-chloro-4-(2oxo-1-(pyridn-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0448] To a solution of example 4b (55 mg) in IMS (5% of methanol inethanol) (10 ml) a 1N solution of NaOH (0.145 ml) was added and reactionmixture was stirred for 1½ hr. The solvent was evaporated and the crudeproduct was triturated in ethyl acetate 2 ml to yield the title compound(38 mg) as a yellow solid.

[0449] m.p.>220° C.

[0450] NMR (DMSO) δ (ppm) 8.96 (d, 1H), 8.32 (dd, 1H), 8.18 (m, 1H),7.40 (m, 1H), 7.12 (d, 1H), 6.78 (d, 1H), 6.38 (dd, 1H), 6.15 (s, 1H),4.46 (m, 1H), 3.83 (m, 2H), 3.3-3.2 (m, 2H), 2.92 (m, 1H), 1.97 (m, 1H).

[0451] IR (Nujol) (cm⁻¹) 3361, 1669.

EXAMPLE 23

[0452](±)-7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicAcid

[0453] To a solution of example 3b (48 mg) in IMS (5% of methanol inethanol) (2 ml) a 0.1N solution of NaOH (1.2 ml) was added and reactionmixture was stirred for 2½ hr. The solution was poured into ethylacetate and washed with a 1N solution of HCl and brine. The organicphase was dried and concentrated to give the crude product which wastriturated in ethyl acetate/petroleum 2 ml/5 ml, to yield the titlecompound (14 mg) as a yellow solid.

[0454] m.p.>130-133° C.

[0455] NMR (DMSO) δ (ppm) 12.64 (s, 1H), 7.38 (t, 2H), 7.30 (d, 2H),7.22 (t, 1H), 6.99 (d, 1H), 6.87 (bd, 1 H), 6.67 (d, 1H), 6.50 (dd, 1H),4.08 (m, 1H), 3.54 (m, 2H), 3.43 (m, 1H), 2.83 (m, 1H), 2.72 (m, 1H),2.58 (1H), 1.93-1.8 (m, 2H)

[0456] IR (Nujol) (cm⁻¹) 3348, 1732, 1717

[0457] MS (m/z) 383

EXAMPLE 24

[0458](±)-7-chloro-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicAcid

[0459] To a solution of intermediate 18 (10 mg) in CH₂Cl₂ (5 ml) a 1Msolution of BCl₃ in hexane (0.1 ml) was added at −78° C. and reactionmixture was stirred for 1½ hr maintaining the temperature between −20and −10° C. The solution was poured into ethyl acetate and washed with a3N solution of HCl and brine. The organic phase was dried with Na₂SO₄and concentrated to give the crude product which was triturated indiethyl ether/petroleum (1 ml/3 ml), to yield the title compound (6 mg)as a yellow solid.

[0460] m.p.>190° C. deg.

[0461] NMR (DMSO) δ (ppm) 12.75 (bs, 1H), 10.50 (bs, 1H), 7.50-7.39 (m,6H), 6.99 (bs, 1H), 6.76 (d, 1H), 6.57 (dd, 1H), 4.15 (m, 1H), 3.77.(m,1H). 3.17 (dd, 1H),.

[0462] IR (Nujol) (cm⁻¹) 3400, 2800, 1746, 1701

EXAMPLE 25

[0463](+/−)-7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicAcid

[0464] To a solution of example 12 (0.027 g) in THF H₂O (3:1) (10 ml)was added LiOH (0.010 g). The mixture was stirred a r.t. for 1 h. Themixture was poured onto a saturated aqueous solution of NH₄Cl (50 ml)and extracted with EA (50 ml), the organic layer was washed with brine(30 ml), dried and concentrated in vacuum. The crude mixture wastriturated with EA to give the title compound as a yellow solid (0.020g). T.l.c. CH/EA (1:1) R_(f)=0.2. IR:3400-2700 (NH, OH), 1660 (C═O)cm⁻¹.

[0465]¹H-NMR:12.63 (sa); 9.94 (sa); 7.65(d); 7.58 (d); 7.20 (d); 6.83(sa); 6.74 (d); 654 (dd); 4.03(m); 3.78(m); 3.70 (m); 3.2-2.6 (m); 2.03(s).

EXAMPLE 26

[0466] (+/−)7-chloro-4-(2-oxo-1-((4-methanesulfonylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicAcid

[0467] To a solution of example 13 (0.023 g) in IMS (5 ml) NaOH (0.120ml) was added. The mixture was stirred a r.t. for 2 h. The mixture waspoured onto a solution of HCl 6N (50 ml) and extracted with EA (50 ml),the organic layer was washed with brine (30 ml), dried and concentratedin vacuum. The crude mixture was chromatographed with Et₂O to give thetitle compound as a yellow solid (0.007 g). T.l.c. CH/EA (1:1)R_(f)=0.2.

[0468] IR:3411 (NH,), 1692, 1651-1583 (C═O), (C═C), 1306-1154 (SO₂)cm⁻¹.

[0469]¹H-NMR: 9.65 (s); 7.69(d); 7.22 (d); 7.20 (d); 6.73 (d); 655 (dd);4.03(m); 3.8-3.5 (m); 3.3-2.9 (m); 2.9 (s).

EXAMPLE 27

[0470]7chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicAcid (Enantiomer A)

[0471] To a solution of intermediate 22 (6.2 g) in THF/H₂O (100 ml, 3/1)at room temperature LiOH (1 g) was added and stirring continued for 1hr. The THF was evaporated and H2O (100 ml) was added. The resultingsolution was washed with diethylether (2×50 ml). The aqueous phase wasacidified until pH=4 with HCl 10% and the product extracted with ethylacetate (2×100 ml) The organic phase was washed with water and brine,dried and evaporated to afford the title compound (4.2 g) as a yellowsolid. m.p.>200° C.

[0472] NMR (DMSO) δ (ppm) 12.62 (bs, 1H); 7.72 (d, 2H), 7.38 (t, 2H),7.20 (d, 1H), 7.13 (t, 1H), 6.86 (d, 1H), 6.74 (d, 1H), 6.54 (dd, 1H),4.06 (m, 1H), 3.86-3.68 (m, 3H), 3.3 (m, 1H), 3.18-2.88 (m, 2H).

[0473] IR (nujol): 3356, 1724

EXAMPLE 28

[0474]7-Chloro-4-(2-oxo-1-phenyl-Δ³-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylicAcid; (Enantiomer A)

[0475] To a solution of intermediate 10 (1.289 g) in THF/H2O (30 ml,3/1) at room temperature LiOH (0.24 g) was added and stirring continuedfor 1 hr. The THF was evaporated and H2O (80 ml) was added. Theresulting solution was washed with diethylether (2×50 ml). The aqueousphase was acidified until pH=4 with HCl 10% and the product was filteredand washed with water (10 ml). The product was dried under vacuum at 60Cfor 12 hrs to obtain 0.734 g as white solid.

[0476] m.p.: 190° C.

[0477] e.e.: 100%

[0478] NMR (DMSO) δ (ppm) 12.86 (bs, 1H); 7.79 (d, 2H), 7.38 (t, 2H),7.11 (d, 1H), 6.81 (d, 1H), 6.77 (d, 1H), 6.64 (s, 1H), 6.46 (dd, 1H);6.34 (s, 1H); 4.46 (m, 1H), 3.82-3.79 (m, 2H), 2.34 (m,₁ H); 1.92 (m, 1H).

[0479] IR (nujol): 3356, 1724

EXAMPLE 29

[0480] Sodium,5,7-Dichloro-4-(2-oxo-1-phenyl-Δ³-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydro-quinoline-2-carboxylicAcid; (Enatiomer A)

[0481] To a solution of intermediate 26a (0.35 g) in THF/H2O (10 ml,3/1) at room temperature LiOH (0.06 g) was added and stirring continuedfor 30 min. The THF was evaporated and H2O (5 ml) was added. Theresulting solution was washed with diethylether (2×50 ml). The aqueousphase was acidified until pH=4 with HCl 10% and the product filtered anddried under vacuum at 60 C for 12 hrs to afford the title compound(0.134 g) as white solid.

[0482] The solid was dissolved in IMS (5% of methanol in ethanol) (10ml) and a 1N solution of NaOH (0.33 ml) was added. To the resultingsuspension diethyl ether was added (10ml) and the solid was filtered,washed with diethyl ether (10 ml) and dried under vacuum for 12 hrs togive the title compound (0.082 g) as a white solid.

[0483] m.p.>220° C.

[0484] NMR (D₂O) δ (ppm) 7.49 (d, 2H); 7.40(t, 2H); 7.23 (t, 1H); 6.74(d, 1H); 6.70 (d, 1H): 6.51 (m, 1H); 4.40-4.35 (m, 2H); 4.11 (m, 1H);3.53 (dd, 1H); 2.18 (m, 1H); 1.74 (td, 1H)

[0485] HPLC Column: Cyclobond I, R,S-Hydroxypropyl ether 25 cm×4.6 mm;Mobile Phase: Methanol=50 20 mM Ammonium Acetate buffer pH 5=50% byvolume; Flow rate: 1 ml/min; Retention time: 12 mins.

EXAMPLE 30

[0486] Sodium5,7-dichloro-4(2-oxo-1-(phenyl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolineCarboxylate (Enatiomer A)

[0487] To a solution of intermediate 26b (0.052 g) in THF/H2O (4 ml,3/1) at room temperature LiOH (0.01 g) was added and stirring continuedfor 30 min. The THF was evaporated and H2O (2 ml) was added. Theresulting solution was washed with diethylether (2×50 ml). The aqueousphase was acidified until pH=4 with HCl 10% and the product was filteredand washed with water (10 ml) and was dried under vacuum at 60° C. for12 hrs to obtain5,7-dichloro-4-(2-oxo-1-(pyridn-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid 0.033 g as a yellow solid. The solid was dissolved inIMS (5% of methanol in ethanol) (5 ml) and a 1N solution of NaOH (0.08ml) was added. After 5 min, the solvent was evaporated and the solidtriturated with diethyl ether (5 ml), filtered, dried under vacuum for12 hrs to give the title compound (0.01 g) as a yellow solid.

[0488] m.p.: >200°

[0489] NMR (DMSO) δ (ppm) 7.74 (d, 2H); 7.39 (t, 2H); 7.15 (t, 1H); 6.76(d, 1H); 6.51 (d, 1H); 6.20 (m, 1H); 4.63 (dd, 1H); 3.78 (m, 2H); 3.41(dd, 1H); 3.18 (m, 1H); 2.35 (dd, 1H); 1.81 (t, 1H).

[0490] IR (nujol): 3363, 1688, 1630, 1586 cm⁻¹

EXAMPLE 31

[0491] (±)-Ethyl7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate(31a)

[0492] (±)-Ethyl7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate(31b)

[0493] To a solution of intermediate 4 (2.2 g) in DMF (50 ml) Pd(PPh₃)₄(244 mg) and TEA (1.2 ml) were added and the resulting solution washeated to 110° C. for 2 h. The crude solution was poured into 200 ml ofethyl acetate and washed first with a saturated solution of NH₄Cl (2×150ml), then with water and brine. The organic phase was dried andconcentrated to give the crude product. Purification by columnchromatography (cyclohexane/dichloromethane/ethyl acetate 50/40/10)Rf=0.41 gave the title compound 31a (540 mg) as an off-white solid.

[0494] m.p.=150-153° C.

[0495] NMR (DMSO) δ (ppm) 7.80 (m, 2H), 7.39 (m, 2H), 7.12 (m, 1H), 6.83(d, 1H), 6.77 (d, 1H), 6.69 (m, 1H), 6.48 (dd, 1H), 6.45 (s, 1H), 4.48(m, 2H), 4.15 (m, 2H), 3.94 (m, 1H), 3.82 (m, 1H), 2.34 (m, 1H), 1.97(m, 1H), 1.20 (t, 3H)

[0496] IR (Nujol) (cm⁻¹) 3385, 1728, 1680

[0497] and the title compound 31b (475 mg) Rf=0.29 as a yellow solid.

[0498] m.p.=152-156° C.

[0499] NMR (DMSO) δ (ppm) 7.72 (m, 2H), 7.39 (m, 2H), 7.20 (d, 1H), 7.16(m, 1H), 6.98 (d, 1H), 6.74 (d, 1H), 6.57 (dd, 1H), 4.29 (dd, 1H), 4.21(m, 1H), 4.02 (m, 1H), 3.93 (m, 1H), 3.82 (m, 1H), 3.69 (m, 1H), 3.20(m, 1H), 2.92 (m, 2H), 0.93 (t, 3H)

EXAMPLE 31a

[0500] (±)-Ethyl7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylate

[0501] To a solution of intermediate 4a (0.1 g) in dry DMF (5 ml)Pd(OAc)2 (10 mg) and TEA (0.026 ml) were added. The mixture was heatedat 110° C. for 2 hrs, then diluted with a saturated solution of NH4Cland extracted with ethyl acetate (2×10 ml).

[0502] The solvent was evaporated and the crude purified by flashchromatography (Cyclohexane/EA 8:2) to afford the title compound as awhite solid (40 mg).

EXAMPLE 31 b

[0503] (±)-Ethyl7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate

[0504] To a solution of intermediate 4b (370 g) in toluene (5.2 lit),Triethylamine (248 ml), Triphenilphosphine (7.4 g) and PdCl₂ (2.52 g)were added. The resulting solution was warmed to 100° C. and stirred for2 h. The suspension was chilled to 20-25° C. and toluene (2.6 ml) wasadded. The reaction mixture was washed with NH₄Cl 8% (3×5.2 lit) andwater (5.2 lit). The organic layer was filtered over a celite pad and itwas washed with toluene (1 lit); then it was distilled under vacuum(T=50° C.; P=60 mbar) to reach 6.3 lit. After cooling to T=20-25° C.,isooctane (5.2 lit) was dropped over 30 min. The precipitate was stirredfor 2 h 30 min then it was filtered and washed with a mixturetoluene/isooctane 1/1 (1.85 lit). The yellow solid was dried in vacuumat T=40° C. for 18 h to obtain the title compound as a yellow solid 210g.

[0505] m.p. 160-162° C.

[0506] NMR (DMSO): 7.72 (m, 2H); 7.39 (m, 2H); 7.20 (d, 2H); 7.15 (m,2H); 6.96 (dd, 1H); 6.74 (d, 1H); 6.57 (dd, 1H); 4.29 (dd, 1H); 4.21 (m,1H); 4.02 (m, 1H); 3.93 (m, 1H); 3.82 (m, 1H); 3.69 (m, 1H); 3.20 (m,1H). 2.92 (m, 2H); 2.92 (m, 2H); 0.93 (t, 3H).

Pharmacy Examples

[0507] A. Capsules/Tablets Active ingredient 20.0 mg Starch 1500 2.5 mgMicrocrystalline 200.0 mg Cellulose Croscarmellose Sodium 6.0 mgMagnesium Stearate 1.5 mg

[0508] The active ingredient is blended with the other excipients. Theblend can be used to fill gelatin capsules or compressed to form tabletsusing appropriate punches. The tablets can be coated using conventionaltechniques and coatings.

[0509] B. Tablets Active ingredient 20.0 mg Lactose 200.0 mgMicrocrystalline 70.0 mg Cellulose Povidone 25.0 mg CroscarmelloseSodium 6.0 mg Magnesium Stearate 1.5 mg

[0510] The active ingredient is blended with lactose, microcrystallinecellulose and part of the croscarmellose sodium. The blend is granulatedwith povidone after dispersing in a suitable solvent (i.e. water). Thegranule, after drying and comminution is blended with the remainingexcipients. The blend can be compressed using appropriate punches andthe tablets coated using conventional techniques and coatings.

[0511] c) Bolus Active ingredient 0.1-32 mg/ml Sodium phosphate 1.0-50.0mg/ml water for injection qs to 1 ml

[0512] The formulation may be packed in glass ampoules or vials andsyringes with a rubber stopper and a plastic/metal overseal (vialsonly).

[0513] D) Infusion Active ingredient 0.01-3.2 mg/ml 5% dextroseinjection qs to 100 ml

[0514] The formulation may be packed in glass vials or plastic bag.

[0515] The affinity of the compound of the invention for the strychnineinsensitive glycine binding site was determined using procedure ofKishimoto H. et al J.

[0516] The pki values obtained with representative compounds of theinvention are given in the following table: Example No pki  1 8.1 14 7.915  7.73 16 7.8 17 8.7 18  7.78 19 8.9 21 7.1 22 7.9 24 7.8 25  7.15 307.7 29 8.7

[0517] The ability of compounds of the invention to inhibit pain inmouse has been assessed in the formalin test as described by Dubuissonand Dennis (Pain, 1977, 4:161-174). In this test 20 μl of 1% formalinwas injected into the plantar surface of the mouse left hind paw. Theamount of time, in seconds, the animals spent licking the injected pawfor the first 5 minutes (early phase) and then from 20 to 60 minutes(late phase) after formalin was used as measurement of the intensity ofpain.

[0518] The compounds of the invention were administered orally 1 hourbefore formalin injection.

[0519] From these results the dose required to reduce the licking timeby 50% expressed as mg/kg is referred to as the ED_(50s) value.

[0520] Representative results obtained for compounds of the inventionwhen given by oral administration are given in the following table: ExNo ED_(50 (mg/kg po)) 21 0.14 17 0.3   2 0.03

[0521] No untoward effects have been observed when compounds of theinvention have been administered to mice at pharmacologically activedoses.

1. A compound of formula (I)

or a salt or a non toxic metabolically labile esters thereof, wherein Yrepresents a carbon atom; Z is the group CH which is linked to the groupY via a double bond and X is CH or Z is methylene or NR₁₁ and X is acarbon atom linked to the group Y via a double bond; A represents a C₁₋₂alkylene chain and which chain may be substituted by one or two groupsselected from C₁₋₆ alkyl optionally substituted by hydroxy, amino,C₁₋₄alkyl amino or C₁₋₄ dialkyl amino or which chain may be substitutedby the group=0; R represents a halogen atom or C₁₋₄ alkyl group; R₁represents a hydrogen, a halogen atom or C₁₋₄ alkyl group; R₂ representsphenyl which may be substituted with up to 3 groups selected fromhalogen, hydrogen, or (CH₂)_(n)R₃ wherein R₃ is COR₄, NR₆R₅, NHCOR₇,NHCONR₉R₈ or NH SO2 R₁₀ group or R₂ is a 5 membered heteroaryl groupcontaining 1 to 3 heteroatoms selected from oxygen, sulphur andnitrogen; or 6 membered heteroaryl group containing 1 to 3 nitrogenatoms R₄ represents an amino, a hydroxyl or C₁₋₄ alkoxy group; R₅ and R₆each independently represents hydrogen or C₁₋₄ alkyl group or R₅ and R₆together with the nitrogen atom to which they are attached represent asaturated 5-7 membered heterocyclic group optionally containing anadditional heroatom selected from oxygen, sulphur or nitrogen R₇represents a hydrogen atom or C₁₋₄alkyl, C₁₋₄alkoxy, or phenyl; R₈represents hydrogen or C₁₋₄ alkyl group; R₉ represents hydrogen,optionally substituted C₁₋₄ alkyl (optionally substituted by one or morehydroxy carboxyl and amino group), phenyl; R₁₁ represents hydrogen orC₁₋₄ alkyl group; R₁₀ represents hydrogen, C₁₋₄ alkyl or a nitrogenprotecting group. n is zero or an integer from 1 to
 2. 2. A compound asclaimed in claim 1 wherein R is chlorine and R_(f) is hydrogen or achlorine atom.
 3. A compound as claimed in claims 1 or 2 wherein A is achain selected from —CH₂—, —(CH₂)₂— or C═O.
 4. A compound as claimed inany of the claims 1-3 wherein Z is CH which is linked to the group Y viaa double bond, a methylene or a NH group.
 5. A compound as claimed inany of the claims 14 wherein R₂ is a group selected from phenyl(optionally substituted by acetylamino, methanesulphonylamino) or3-pyridyl.
 6. A compound as claimed in any of the claims 1-5 wherein R₂represents phenyl.
 7. A compound as claimed in any of the claims 1-6wherein A is a chain selected from —CH₂—, —(CH₂)₂—, and Z is the groupCH which is linked to the group Y via a double bond, or a methylenegroup, or A is C═O and Z is a NH group, R is chlorine, R_(f) is chlorineor hydrogen and R₂ is phenyl (optionally substituted by acetylamino ormethanesulphonylamino) or 3-pyridyl. 8.(±)7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, physiologically acceptable salts or non toxicmetabolically labile esters thereof.
 9. Sodium (±)7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)1,2,3,4-tetrahydro-2-quinolinecarboxylate.
 10. (−) Sodium7-chloro-4-(2-oxo-1-phenyl-3-pyrrolidinylidene)1,2,3,4-tetrahydro-2-quinolinecarboxylate. 11.(±)7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid, physiologically acceptable salts or non toxicmetabolically labile esters thereof.
 12. Sodium(±)7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate.13. (−)Sodium7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate.14. (+) Sodium7-chloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydro-2-quinolinecarboxylate.15. A compound selected from:(±)-7-chloro-4-(1-(3-pyridin)-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid,(±)-7-chloro-4-(1-phenyl-Δ³-5,6-dihydro-pyridin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxlicacid,(±)-5,7-dichloro-4-(1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid,(+/−)-7-chloro-4-(1-(4-acetylamino)-1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid,(+/−)7-chloro-4-(1-(4-methanesulfonylamino)-1-phenyl-Δ³-pyrrolin-2-one-3yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid,(±)-7-chloro-4-(2-oxo-1-phenyl-3-piperidinylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid,(±)-7-chloro-4-(2,5-dioxo-1-phenyl-imidazolidin-4-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid,(±)-7-chloro-4-(2-oxo-1-pyridin-3yl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylate,(±)-7-chloro-4-(2-oxo-1-(4-acetylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid, (±)7-chloro-4-(2-oxo-1-((4-methanesulfonylamino)phenyl-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylicacid,5,7-dichloro-4-(2-oxo-1-(phenyl)-pyrrolidin-3-ylidene)-1,2,3,4-tetrahydro-2-quinolinecarboxylic acid,5,7-dichloro-4-(2-oxo-1-phenyl-Δ3-pyrrolin-2-one-3-yl)-1,2,3,4-tetrahydroquinoline-2-carboxylicacid; and physiologically acceptable salts (e.g. sodium salts),non-toxic metabolically labile esters or enantiomers thereof.
 16. Acompound as claimed in any of claims 1-15 for use in therapy.
 17. Theuse of a compound as claimed in any of claims 1-15 in the manufacturingof a therapeutic agent for antagonising the effects of excitatory aminoacids on the NMDA receptor complex.
 18. A pharmaceutical compositioncomprising a compound as claimed in any of claims 1-15 in admixture withone or more physiologically acceptable carriers or excipients.
 19. Amethod of treatment of a mammal including man for conditions whereantagonising the effects of excitatory amino acids on the NMDA receptorcomplex is of therapeutic benefit comprising administration of aneffective amount of a compound as claimed in any of claims 1 to
 16. 20.A process for the preparation of compounds as claimed in any of theclaims 1-15 which comprises cyclising a compound of formula (II) inwhich R, R₁, R₂, A, X, Y, Z have the meanings defined in claim 1 and R₁₂is a carboxylic protecting group, R₁₃ represents a bromine or iodineatom, R₁₄ represents hydrogen or a nitrogen protecting group,

followed where necessary or desired by one or more of the followingsteps: (i) removal of a protecting group, (ii) isolation of the compoundas a salt thereof; (iii) conversion of a compound of formula (I) or asalt thereof into a metabolically labile ester thereof, (iv) separationof a compound of formula (I) or a derivative thereof into theenantiomers thereof.